PSMF1 Human

What is PSMF1 and what is its molecular function in human cells?

PSMF1 (Proteasome Inhibitor PI31 Subunit) encodes a highly conserved 31-kDa protein that is ubiquitously expressed across human tissues. It functions as a key regulator of the proteasome system, which is essential for protein quality control and degradation . PSMF1 exhibits dual functionality in proteasome regulation. In vitro studies demonstrate that PSMF1 can inhibit peptide hydrolysis by the 20S proteasome through its C-terminal proline-rich domain, either through direct binding or competitive binding to the 20S activating particles PA700 and PA28 . Conversely, PSMF1 can also stimulate 26S proteasome-mediated proteolysis in vitro .

The in vivo functions of PSMF1 are particularly significant in neuronal contexts. It mediates fast transport of proteasomes between neurosomes and synapses, which is required for synapse maintenance and neuronal survival as demonstrated in both Drosophila and mouse models . This transportation function highlights the critical role PSMF1 plays in maintaining neuronal health and function, particularly in regions with high metabolic demands such as synapses.

Further research has demonstrated that PSMF1 inactivation in Drosophila and mice causes accumulation of poly-ubiquitinated aggregates, which are exclusive substrates of the 26S proteasome . This finding indicates that functional PSMF1 is essential for proper protein degradation pathways, with its dysfunction leading to proteotoxic stress—a hallmark of many neurodegenerative conditions.

How do PSMF1 variants contribute to neurodegenerative disorders in humans?

PSMF1 variants have recently been established as causative factors in a spectrum of neurodegenerative disorders. Extensive clinical and genetic studies across 15 unrelated families of diverse ethnicities (European, Asian, and African ancestry) have identified that biallelic PSMF1 variants co-segregate with phenotypes ranging from early-onset Parkinson's disease to severe perinatal neurological manifestations .

The pathogenic mechanisms involve several interconnected cellular pathways:

• Disruption of the ubiquitin-proteasome system: PSMF1 variants impair proteasomal function, leading to the accumulation of protein aggregates that can be toxic to neurons, particularly dopaminergic neurons in the substantia nigra pars compacta .

• Mitochondrial dysfunction: Patient-derived fibroblasts with PSMF1 variants show impaired mitochondrial membrane potential, disrupted mitochondrial dynamics, and defective mitophagy . These mitochondrial abnormalities likely contribute to bioenergetic failure in neurons.

• Protein interaction network disturbances: PSMF1 interacts with several proteins implicated in neurodegeneration, including:

  • F-box only protein 7 (FBXO7), whose genetic defects cause juvenile-onset parkinsonism

  • Valosin-containing protein (VCP), associated with amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease

The ablation of the PSMF1-FBXO7 heterodimer by FBXO7 missense variants leads to reduced expression and stability of both PSMF1 and FBXO7, resulting in both proteasomal and mitochondrial dysfunction . This suggests that the interaction between PSMF1 and FBXO7 is critical for maintaining cellular homeostasis.

What is the genotype-phenotype correlation in PSMF1-related disorders?

Research has established a clear genotype-phenotype correlation in PSMF1-related disorders, with three distinct clinical subgroups corresponding to specific types of genetic variants . This correlation provides valuable insights for clinical diagnosis, prognosis, and potential therapeutic development.

This stratification demonstrates that the severity of PSMF1-related disorders correlates with the degree of functional impairment caused by different variants . Missense variants that partially impair PSMF1 function result in a milder phenotype manifesting as early-onset PD, while complete loss-of-function variants cause severe developmental abnormalities incompatible with postnatal survival.

What experimental models have been developed to study PSMF1 function?

Multiple experimental models have been developed to investigate PSMF1 function and its role in neurodegenerative processes. These models provide complementary insights into the molecular mechanisms and phenotypic consequences of PSMF1 dysfunction:

• Patient-derived fibroblasts:
  Patient-derived fibroblasts have been instrumental in studying the effects of PSMF1 variants on cellular functions, particularly mitochondrial dynamics and health . These cellular models allow for direct assessment of how pathogenic variants affect:

  • Mitochondrial membrane potential

  • Mitochondrial morphology and dynamics

  • Mitophagy (the elimination of damaged mitochondria)

  • Proteasomal function

• Drosophila models:
  Psmf1 knockdown Drosophila models have been developed that exhibit age-dependent motor impairment, recapitulating aspects of human PSMF1-related disorders . Studies in Drosophila have demonstrated that:

  • PSMF1 inactivation causes accumulation of poly-ubiquitinated aggregates

  • PSMF1 is required for synapse maintenance and neuronal survival

  • FBXO7 prevents PSMF1 from proteolytic cleavage, suggesting an important regulatory mechanism

• Mouse models:
  Conditional Psmf1 knockout mice exhibit age-dependent motor impairment with diffuse gliosis . These models have shown that:

  • Complete loss of PSMF1 function during development is lethal

  • Conditional knockout in specific tissues can recapitulate aspects of human disease

  • PSMF1 deficiency leads to neuroinflammation, as evidenced by gliosis

These models collectively provide a multimodal approach to understanding PSMF1 biology and pathology, from molecular interactions to organismal phenotypes. They serve as valuable platforms for testing potential therapeutic strategies targeting PSMF1-related pathways .

What methodologies are most effective for identifying and validating novel PSMF1 variants?

Identifying and validating novel PSMF1 variants requires a comprehensive approach combining multiple complementary methodologies:

Genetic Identification Methods:

• Exome/Genome Sequencing: The initial identification of PSMF1 variants in the reported cases was achieved through trio exome sequencing, which allows for the detection of rare variants in affected individuals and their parents .

• Autozygosity Mapping: This approach has proven valuable for families with consanguinity. Studies have shown that the PSMF1 locus lies within regions of homozygosity (ROH) in affected individuals from consanguineous families carrying homozygous PSMF1 variants .

• Segregation Analysis: This critical validation step confirms that biallelic PSMF1 variants co-segregate with neurological disease phenotypes. Research has shown that parents of affected individuals are heterozygous for one PSMF1 variant, while unaffected siblings are either heterozygotes or wild-type homozygotes .

Variant Pathogenicity Assessment:

• Population Frequency Analysis: All pathogenic PSMF1 variants identified were absent or ultra-rare in the heterozygous state and not reported in the homozygous state in gnomAD, except for the p.Arg242His variant which had low frequency and four homozygous entries .

• In Silico Prediction Tools: Multiple computational tools should be employed:

  • For coding variants: CADD (CADD Phred range for known pathogenic variants: 22.3-37), PolyPhen2, SIFT4G, PROVEAN, and MutationTaster

  • For splice variants: SpliceSiteFinder-like, MaxEntScan, NNSPLICE, GeneSplicer, SpliceAI, and AbSplice

• Evolutionary Conservation Analysis: PSMF1 missense variants identified in affected individuals showed strong evolutionary conservation across species down to invertebrates, indicating functional importance of these residues .

• Structural Modeling: Tools like AlphaFold2 can be used to model the three-dimensional organization of protein complexes and assess the potential impact of variants. For example, modeling revealed that the p.Leu53Met variant likely disrupts interactions within the PSMF1/FBXO7 heterotetrameric complex .

Functional Validation:

• Patient-Derived Cell Studies: Fibroblasts from affected individuals have been used to demonstrate the functional impact of PSMF1 variants on mitochondrial function, providing direct evidence of pathogenicity .

• Animal Model Validation: Introducing variants into Drosophila or mice and assessing for phenotypic similarities to human disease provides additional validation of variant pathogenicity .

This multi-faceted approach ensures robust identification and validation of PSMF1 variants associated with neurodegenerative disorders.

How do PSMF1 variants affect mitochondrial function, and what techniques reveal these mechanisms?

PSMF1 variants have been shown to significantly impair mitochondrial function through multiple interconnected mechanisms. Research using patient-derived fibroblasts has revealed detailed insights into how PSMF1 dysfunction affects mitochondrial health and dynamics .

Affected Mitochondrial Processes:

• Mitochondrial Membrane Potential:

  • Patient fibroblasts with PSMF1 variants demonstrate reduced mitochondrial membrane potential

  • This impairment affects the proton gradient necessary for ATP production, potentially leading to bioenergetic deficits particularly detrimental to neurons with high energy demands

• Mitochondrial Dynamics:

  • Abnormalities in mitochondrial fusion and fission processes have been observed in cells with PSMF1 variants

  • These disruptions can lead to accumulation of fragmented, dysfunctional mitochondria

• Mitophagy:

  • PSMF1 variants impair mitophagy, the process by which damaged mitochondria are eliminated

  • Defective mitophagy results in the persistence of dysfunctional mitochondria, contributing to cellular stress

Research Techniques for Mitochondrial Assessment:

• Live Cell Imaging:

  • Mitochondria-specific fluorescent dyes (e.g., TMRM, MitoTracker) can be used to visualize mitochondrial morphology and membrane potential in real-time

  • Time-lapse microscopy enables tracking of dynamic processes like fusion, fission, and transport

• Flow Cytometry:

  • Quantitative assessment of mitochondrial membrane potential across large cell populations

  • Can be combined with cell type-specific markers for heterogeneous samples

• Mitophagy Assays:

  • Mitophagy-specific reporter systems (e.g., mt-Keima, mito-QC) allow for monitoring mitophagy flux

  • Immunoblotting for PINK1, Parkin, and LC3-II can assess mitophagy pathway activation

• Electron Microscopy:

  • Ultrastructural analysis of mitochondrial morphology and integrity

  • Can reveal detailed abnormalities in cristae structure and mitochondrial-ER contacts

• Seahorse Metabolic Analysis:

  • Measures oxygen consumption rate (OCR) and extracellular acidification rate (ECAR)

  • Provides functional assessment of mitochondrial respiratory capacity

The connection between PSMF1 and mitochondrial function likely involves its interaction with proteins like FBXO7, which has established roles in mitophagy. The PSMF1-FBXO7 complex may regulate the clearance of damaged mitochondria, explaining why PSMF1 variants lead to mitochondrial dysfunction . These findings suggest that mitochondrial dysfunction is a key pathogenic mechanism in PSMF1-related neurodegeneration, consistent with the central role of mitochondrial health in neuronal survival.

What is the structural basis for PSMF1 protein interactions with neurodegeneration-associated proteins?

PSMF1 forms critical interactions with several proteins implicated in neurodegeneration. Understanding the structural basis of these interactions provides insights into pathogenic mechanisms and potential therapeutic targets .

PSMF1-FBXO7 Interaction:

PSMF1 is a high-affinity binding partner of F-box only protein 7 (FBXO7), whose genetic defects cause juvenile-onset PD/parkinsonism . This interaction occurs through their respective N-terminal FBXO7/PSMF1 (FP) domains .

Structural modeling using AlphaFold2 has revealed that the PSMF1/FBXO7 complex forms a heterotetrameric structure . Specific residues like p.Leu53 in PSMF1 sit directly on the interface between PSMF1 monomers within this complex, forming hydrogen bonds with p.Val6 and p.Ala9 . The p.Leu53Met variant identified in patients likely disrupts these interactions, weakening the quaternary structure of the predicted heterotetramer .

Functionally, FBXO7 prevents PSMF1 from proteolytic cleavage in Drosophila and mouse models, suggesting that FBXO7 loss may cause proteasomal impairment by PSMF1 inactivation . In human fibroblasts, disruption of this heterodimer by an FBXO7 missense variant leads to reduced expression and stability of both PSMF1 and FBXO7, as well as proteasomal and mitochondrial dysfunction .

PSMF1-VCP Interaction:

PSMF1 directly binds valosin-containing protein (VCP) , whose defective functions are linked to amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease . This interaction appears to have functional consequences for proteasomal regulation, as VCP and PSMF1 act as in vitro up- and down-regulators of proteasomal activity, respectively .

Research Methods for Structural Analysis:

• X-ray Crystallography and Cryo-EM:

  • Can provide high-resolution structures of PSMF1 complexes

  • Reveals atomic details of interaction interfaces

• Computational Modeling:

  • Tools like AlphaFold2 can predict protein structures and complexes

  • Particularly valuable for modeling the effects of disease-causing variants

• Protein-Protein Interaction Assays:

  • Yeast two-hybrid and mammalian two-hybrid assays

  • Co-immunoprecipitation followed by mass spectrometry

  • FRET/BRET to study interactions in living cells

• Mutagenesis Studies:

  • Site-directed mutagenesis to identify critical residues for interactions

  • Can validate computational predictions about interaction interfaces

These structural insights are crucial for understanding how PSMF1 variants disrupt protein interactions and cellular functions, potentially leading to targeted therapeutic approaches for PSMF1-related disorders.

What are the challenges in designing disease models that accurately recapitulate PSMF1-related neurodegeneration?

Developing disease models that faithfully recapitulate PSMF1-related neurodegeneration presents several significant challenges that researchers must address:

Biological Challenges:

• Genotype-Phenotype Complexity:

  • PSMF1 variants cause a phenotypic spectrum ranging from early-onset PD to perinatal lethality

  • Creating models that reflect this spectrum requires multiple approaches targeting different variant types

  • Complete PSMF1 knockout is likely lethal during development, necessitating conditional or partial knockdown approaches

• Cell Type Specificity:

  • While PSMF1 is ubiquitously expressed, neuronal populations show differential vulnerability

  • Dopaminergic neurons in the substantia nigra are particularly affected in PD-like presentations

  • Models must capture this selective vulnerability despite ubiquitous protein expression

• Age-Dependent Manifestations:

  • PSMF1-related PD typically manifests in the second to fifth decade of life

  • Animal models may need accelerated aging or long observation periods to develop relevant phenotypes

  • Both Drosophila and mouse models show age-dependent motor impairment, consistent with human disease

• Species-Specific Differences:

  • Differences in lifespan, metabolism, and neural architecture between humans and model organisms

  • Human-specific protein interactions or regulatory mechanisms may not be fully conserved in animal models

Methodological Challenges:

• Modeling Specific Variants:

  • Introducing precise human variants rather than gene knockouts/knockdowns

  • CRISPR-Cas9 gene editing allows for introduction of specific variants but may have off-target effects

  • Homology between human PSMF1 and its orthologs in model organisms may affect variant introduction

• Tissue-Specific Expression:

  • Conditional knockout systems (e.g., Cre-loxP in mice) can target specific tissues/cell types

  • Temporal control systems (e.g., tamoxifen-inducible) allow for variant expression at specific developmental stages

  • Balancing between global effects and cell type-specific manifestations

• Phenotypic Assessment:

  • Developing sensitive assays for motor function, cognitive abilities, and neuronal integrity

  • Correlating behavioral phenotypes with cellular and molecular changes

  • Longitudinal studies to capture progressive nature of disease

Promising Approaches:

• Patient-Derived Models:

  • iPSC-derived neurons from patients with PSMF1 variants

  • Organoids to study three-dimensional tissue architecture and cell-cell interactions

  • Direct reprogramming of patient fibroblasts to induced neurons

• Complementary Model Systems:

  • Using multiple models (Drosophila, mouse, cellular) in parallel

  • Each model addresses different aspects of disease biology

  • Current research has successfully developed both Drosophila and mouse models exhibiting age-dependent motor impairment

• Multi-Omics Approaches:

  • Combining transcriptomics, proteomics, and metabolomics

  • Provides comprehensive view of molecular changes

  • Helps identify conserved disease signatures across models

Despite these challenges, current models have already provided valuable insights into PSMF1 function and the consequences of its disruption . Further refinement of these models will continue to advance our understanding of PSMF1-related neurodegeneration.

How can high-throughput screening approaches identify potential therapeutic targets for PSMF1-related disorders?

High-throughput screening (HTS) approaches offer promising strategies to identify therapeutic targets and candidate compounds for PSMF1-related disorders. These methods can accelerate the discovery process by systematically evaluating large numbers of interventions.

Target Identification Strategies:

• Genetic Interaction Screens:

  • CRISPR-Cas9 or RNAi screens can identify genetic modifiers of PSMF1-related phenotypes

  • Synthetic lethal screens in cells expressing PSMF1 variants may reveal critical dependencies

  • Suppressor screens can identify genes that, when modulated, rescue PSMF1-related defects

  • Target pathways might include proteasome function enhancers or mitochondrial health promoters, given the established role of PSMF1 in these processes

• Protein-Protein Interaction Screens:

  • BioID or APEX proximity labeling to identify the PSMF1 interactome

  • Affinity purification-mass spectrometry to define protein complexes

  • Yeast two-hybrid screens to identify novel interaction partners

  • Special focus should be placed on interactions with FBXO7 and VCP, known PSMF1 binding partners implicated in neurodegeneration

• Transcriptomic and Proteomic Profiling:

  • RNA-seq and proteomics of patient-derived cells or model systems

  • Identifies dysregulated pathways that could be targeted therapeutically

  • Comparison across different PSMF1 variants may reveal variant-specific and common pathways

Compound Screening Approaches:

• Phenotypic Screens:

  • High-content imaging of mitochondrial morphology and function in PSMF1-variant cells

  • Monitoring proteasome activity using fluorescent reporters

  • Assessing neuronal survival in primary culture models

  • Compounds that restore mitochondrial membrane potential or dynamics would be particularly relevant based on the identified mitochondrial defects in PSMF1 variant cells

• Target-Based Screens:

  • In vitro assays measuring PSMF1-FBXO7 or PSMF1-VCP interaction strength

  • Proteasome activity assays in the presence of PSMF1 variants

  • Mitophagy induction assays using fluorescent reporters

• In Vivo Screens:

  • Medium-throughput screening in Drosophila PSMF1 models

  • Compound libraries can be administered in food

  • Motor function and lifespan as primary readouts

  • The established Drosophila models showing age-dependent motor impairment provide an excellent platform for such screens

Computational Approaches:

• Virtual Screening:

  • Structure-based virtual screening targeting PSMF1 interaction interfaces

  • Molecular docking to identify compounds that could stabilize PSMF1 structure

  • AlphaFold2-generated models of PSMF1 complexes can guide these efforts

• Network-Based Drug Repurposing:

  • Analyzing gene expression signatures induced by PSMF1 variants

  • Identifying approved drugs that reverse these signatures

  • Connectivity Map (CMap) or similar approaches

• Machine Learning Approaches:

  • Predicting compound efficacy based on chemical structures and biological data

  • Transfer learning from related neurodegenerative disorders

Given the clear genotype-phenotype correlation in PSMF1-related disorders , different therapeutic strategies may be needed for different variant classes. Missense variants causing PD might benefit from approaches enhancing residual PSMF1 function, while more severe variants might require bypass strategies targeting downstream pathways.

What is the relationship between PSMF1 dysfunction and selective neuronal vulnerability in Parkinson's disease?

The selective vulnerability of specific neuronal populations, particularly dopaminergic neurons in the substantia nigra pars compacta, is a hallmark of Parkinson's disease. Research on PSMF1 provides new insights into the mechanisms underlying this selective vulnerability .

Molecular Basis for Selective Vulnerability:

• Proteostasis Requirements:

  • Dopaminergic neurons have high proteostatic demands due to their complex morphology and high energy needs

  • PSMF1 plays a critical role in proteasome regulation and protein breakdown

  • PSMF1 dysfunction leads to accumulation of poly-ubiquitinated aggregates in model organisms

  • Dopaminergic neurons may be particularly sensitive to proteostatic stress induced by PSMF1 variants

• Mitochondrial Dependency:

  • Dopaminergic neurons have high energy demands and rely heavily on mitochondrial function

  • PSMF1 variants impair mitochondrial membrane potential, dynamics, and mitophagy

  • Mitochondrial dysfunction has been solidly recognized as a pivotal driver of neurodegeneration in PD

  • The combination of high energy demands and PSMF1-induced mitochondrial dysfunction may explain selective vulnerability

• Synaptic Maintenance:

  • PSMF1 mediates fast transport of proteasomes between neurosomes and synapses

  • It is required for synapse maintenance and neuronal survival in Drosophila and mice

  • Neurons with extensive synaptic connections may be more vulnerable to PSMF1 dysfunction

• Interaction with PD-Associated Proteins:

  • PSMF1 is a high-affinity binding partner of FBXO7, whose genetic defects cause juvenile-onset PD/parkinsonism

  • The PSMF1-FBXO7 interaction may be particularly important in vulnerable neuronal populations

  • Disruption of this interaction affects both proteasomal and mitochondrial function

Evidence from Human Studies and Disease Models:

• Human Neuropathology:

  • Patients with PSMF1-related early-onset PD show clinical features typical of dopaminergic neuron loss in the substantia nigra

  • The good initial response to levodopa further supports the selective involvement of the nigrostriatal dopaminergic system

• Animal Models:

  • Psmf1 knockdown Drosophila and conditional knockout mice exhibit age-dependent motor impairment

  • Mouse models show diffuse gliosis, indicating neuroinflammation

  • These models provide opportunities to study the progression of neurodegeneration in specific brain regions

• Cellular Models:

  • Patient-derived fibroblasts show mitochondrial dysfunction

  • iPSC-derived neurons could further elucidate cell type-specific vulnerabilities

Potential Compensatory Mechanisms:

• Regional Expression Differences:

  • Variation in PSMF1 expression levels across brain regions

  • Different ratios of PSMF1 to interacting partners (FBXO7, VCP)

  • Alternative proteasome regulators that may compensate in some regions but not others

• Metabolic Adaptations:

  • Some neuronal populations may have greater metabolic flexibility

  • Ability to shift between oxidative phosphorylation and glycolysis

  • Differential capacity for mitophagy or mitochondrial biogenesis

Understanding the basis of selective vulnerability in PSMF1-related disorders may provide insights applicable to sporadic PD and other neurodegenerative conditions. It also highlights potential therapeutic targets focused on enhancing proteasome function or mitochondrial health specifically in vulnerable neuronal populations.

What are the future directions for PSMF1 research in understanding and treating neurodegenerative disorders?

The identification of PSMF1 as a gene implicated in PD and early human neurodegeneration opens numerous avenues for future research with potential therapeutic implications . Key future directions include:

Mechanistic Understanding:

• Detailed Structural Studies:

  • High-resolution structures of PSMF1 alone and in complex with interacting partners

  • Structural basis for variant effects on protein function

  • Structure-guided design of therapeutic molecules that could stabilize PSMF1 function

• Comprehensive Cellular Pathway Mapping:

  • Systematic analysis of how PSMF1 variants affect proteasome assembly and function

  • Integration of PSMF1 into known PD pathways involving mitochondria, protein quality control, and synaptic maintenance

  • Temporal analysis of cellular events following PSMF1 dysfunction

• Advanced Animal Models:

  • Development of knock-in models carrying specific human PSMF1 variants

  • Conditional and inducible models to study age-dependent effects

  • Humanized mouse models to better recapitulate human disease

Translational Research:

• Biomarker Development:

  • Identification of blood, CSF, or imaging biomarkers specific to PSMF1-related disorders

  • Biomarkers that correlate with disease progression or treatment response

  • Potential application to broader PD populations

• Therapeutic Target Validation:

  • Validation of targets identified through genetic or chemical screens

  • Testing of combined approaches targeting multiple pathways

  • Preclinical testing in appropriate disease models

• Clinical Studies:

  • Natural history studies of PSMF1-related disorders

  • Development of clinical outcome measures sensitive to disease progression

  • Early-phase clinical trials for promising therapeutic approaches

Technological Innovations:

• Advanced iPSC Models:

  • Brain organoids from patients with different PSMF1 variants

  • Midbrain organoids specifically modeling dopaminergic neuron vulnerability

  • Co-culture systems to study cell-cell interactions

• In Vivo Imaging:

  • Development of PET ligands for proteasome or mitochondrial function

  • Longitudinal imaging studies in animal models and patients

  • Correlation of imaging findings with clinical progression

• Single-Cell Multi-Omics:

  • Single-cell transcriptomics, proteomics, and metabolomics in brain tissue

  • Cell type-specific responses to PSMF1 dysfunction

  • Identification of vulnerable and resistant cell populations

Broader Implications:

• Connection to Sporadic PD:

  • Investigation of PSMF1 expression or function in sporadic PD

  • Common pathways between PSMF1-related and idiopathic PD

  • Potential for PSMF1-targeting therapies in broader PD populations

• Therapeutic Leverage Points:

  • Enhancing proteasome function in neurodegenerative disorders

  • Improving mitochondrial health and mitophagy

  • Stabilizing protein interactions disrupted by PSMF1 variants

• Integration with Other Genetic Forms of PD:

  • Comparative studies with other genetic forms of PD (LRRK2, Parkin, PINK1, etc.)

  • Identification of convergent and divergent pathways

  • Development of pathway-specific therapeutic approaches

The study of PSMF1-related disorders represents an important opportunity to gain insights into fundamental mechanisms of neurodegeneration. Like the identification of LRRK2 variants in PD, which has led to the development of LRRK2 inhibitors now in clinical trials, the discovery of PSMF1's role may foster the identification of biomarkers and development of disease-modifying strategies for PD and related disorders .