FAM19A5 Human

What is FAM19A5 and where is it primarily expressed in humans?

FAM19A5 (Family with sequence similarity 19 member A5) is a novel chemokine-like peptide and secreted protein predominantly expressed in the central nervous system. It is one of five highly homologous family members of the FAM19A family . In the brain, FAM19A5 exhibits particularly high expression in the hippocampus, as demonstrated in rodent models where it has been detected in the hippocampus, hypothalamic paranucleus, and suprabranchial nucleus . The protein contains 43 amino acids at its N-terminus that function as its main signal peptides, confirming its role as a secreted factor .

How should researchers collect and measure FAM19A5 levels in human subjects?

For human studies, FAM19A5 levels can be effectively measured in serum using sandwich enzyme-linked immunosorbent assay (ELISA) techniques . When designing a study to measure FAM19A5:

• Collect serum samples following standard clinical protocols

• Store samples appropriately to maintain protein integrity

• Use validated ELISA kits specifically designed for human FAM19A5 detection

• Include appropriate controls and standardization markers

• Consider potential confounding factors like age, gender, medication use, and comorbidities

Research indicates that quantifying serum FAM19A5 levels provides valuable insights, particularly in conditions like vascular dementia, where significant differences have been observed between patients and controls .

What is the current understanding of FAM19A5's role in normal brain function?

Based on available research, FAM19A5 appears to play important roles in:

• Synapse formation and maintenance, as evidenced by studies showing reduced spine density following FAM19A5 loss

• Glutamatergic signaling pathways that influence neuronal activity

• Fear response and emotional processing pathways, with FAM19A5-deficient mice showing altered fear conditioning responses

• Cognitive function regulation, particularly in spatial learning and memory processes

Interestingly, selective overexpression of FAM19A5 in the mouse hippocampus has been shown to alleviate chronic stress-related spatial learning and memory impairment, suggesting a neuroprotective role under certain conditions .

How does FAM19A5 contribute to Alzheimer's disease pathogenesis at the molecular level?

Evidence suggests FAM19A5 plays a significant role in Alzheimer's disease (AD) pathophysiology, particularly in relation to amyloid-beta (Aβ) plaque formation. Research using mouse models has demonstrated that partial FAM19A5 deficiency (APP/PS1/FAM19A5+/LacZ mice) leads to significantly lower Aβ plaque density compared to control APP/PS1 mice . This suggests FAM19A5 may facilitate Aβ aggregation or impair clearance mechanisms.

The molecular mechanisms may involve:

• Potential interaction with proteins involved in Aβ processing or clearance

• Influence on neuroinflammatory pathways that affect plaque formation

• Modulation of synaptic function and neuronal health

• Interaction with LRRC4B protein, which could affect neuronal signaling pathways

Researchers should design experiments to investigate these pathways specifically, using techniques like co-immunoprecipitation, proximity ligation assays, and functional studies in relevant cell types.

What is the correlation between serum FAM19A5 levels and cognitive impairment in various neurodegenerative conditions?

Research has established significant correlations between FAM19A5 levels and cognitive function, particularly in vascular dementia (VaD):

Multiple regression analysis has identified serum FAM19A5 level as an independent predictive risk marker for cognitive function in VaD patients (β = 0.419, p = 0.031), even after adjusting for demographic and clinical baseline characteristics .

Research methodologies to further investigate this relationship should include:

• Longitudinal studies tracking FAM19A5 levels and cognitive decline

• Multimodal approaches combining serum biomarkers with neuroimaging

• Comparison across different types of dementia and neurodegenerative conditions

• Correlation with other established biomarkers of neurodegeneration

What is the therapeutic potential of targeting FAM19A5 in Alzheimer's disease, and what research approaches show the most promise?

Anti-FAM19A5 immunotherapy has shown promising results in preclinical studies:

• Antibody Development and Characterization: Researchers have developed antibodies targeting FAM19A5 that demonstrate significant therapeutic potential .

• Administration Protocols: In mouse models, effective administration includes:

  • Intravenous (IV) delivery at doses of 5-10 mg/kg

  • Treatment regimens of four times weekly administration

  • Pharmacokinetic studies showing plasma half-life of 6.8 days and brain half-life of 17.3 days

• Cognitive Outcomes: Administration of FAM19A5 antibodies to AD mouse models resulted in:

  • Improved performance in Y-maze and passive avoidance tests

  • Enhanced novel object recognition performance

  • Increased spontaneous alternation behavior indicating improved spatial working memory

• Promising Research Directions:

  • Optimization of antibody design for enhanced blood-brain barrier penetration

  • Combination therapies with established anti-amyloid approaches

  • Development of small molecule modulators of FAM19A5 activity

  • Investigation of potential delivery systems for targeted brain delivery

How do researchers differentiate between correlation and causation when studying FAM19A5 in human neurological disorders?

Establishing causative relationships between FAM19A5 and neurological conditions requires rigorous experimental approaches:

• Genetic Association Studies:

  • Genome-wide association studies (GWAS) examining FAM19A5 variants and disease risk

  • Mendelian randomization approaches to establish causal relationships

  • Familial studies in rare genetic cases with FAM19A5 mutations

• Animal Model Validation:

  • Use of knockout models (e.g., FAM19A5-LacZ KI mice)

  • Conditional and inducible knockout models to distinguish developmental from acute effects

  • Humanized mouse models expressing human FAM19A5 variants

• Mechanistic Studies:

  • In vitro studies using patient-derived cells

  • CRISPR-Cas9 mediated gene editing to establish causality

  • Time-course experiments to establish temporal relationships

• Biomarker Development:

  • Longitudinal studies tracking FAM19A5 levels before symptom onset

  • Integration with other established biomarkers

  • Machine learning approaches to identify predictive patterns

Researchers should design experiments that can distinguish whether altered FAM19A5 levels are a cause, consequence, or merely a correlate of disease processes.

What are the optimal techniques for studying FAM19A5-protein interactions in the context of neurodegeneration?

Several complementary approaches are recommended for investigating FAM19A5 interactions:

• Computational Structural Biology:

  • AlphaFold2 modeling of FAM19A5 and potential binding partners

  • Generate paired multiple sequence alignments (paired MSAs) following established protocols

  • Use structure prediction tools to identify potential interaction surfaces

• Protein-Protein Interaction Assays:

  • Co-immunoprecipitation experiments with candidate binding partners

  • Proximity ligation assays to confirm interactions in situ

  • Bioluminescence resonance energy transfer (BRET) or fluorescence resonance energy transfer (FRET) for real-time interaction dynamics

  • Surface plasmon resonance to measure binding kinetics

• Structural Analysis:

  • X-ray crystallography of FAM19A5 complexes

  • Cryo-electron microscopy for larger complexes

  • Nuclear magnetic resonance (NMR) for solution-state dynamics

  • Identification of critical binding residues through systematic mutagenesis

• Functional Validation:

  • Assess the impact of disrupting specific interactions on cellular functions

  • Use of peptide mimetics to block specific interaction sites

  • CRISPR-Cas9 gene editing to create specific mutations in binding interfaces

The LRRC4B protein has been identified as an interaction partner for FAM19A5, with structural studies using AlphaFold2 revealing important details about this complex . Identifying salt bridges and other key interaction motifs can guide the development of therapeutic approaches targeting specific protein-protein interactions.

What are the key considerations when designing experiments to investigate FAM19A5 in human neural tissues?

When designing experiments with human neural tissues:

• Tissue Collection and Processing:

  • Establish standardized protocols for post-mortem tissue collection

  • Consider regional variations in FAM19A5 expression

  • Process tissues rapidly to preserve protein integrity

  • Create matched sample sets across disease states and controls

• Expression Analysis:

  • Use RNAscope or single-cell RNA sequencing for precise cellular localization

  • Employ quantitative immunohistochemistry with validated antibodies

  • Consider laser capture microdissection for region-specific analysis

  • Compare protein and mRNA levels to identify post-transcriptional regulation

• Functional Studies:

  • Use patient-derived induced pluripotent stem cells (iPSCs) differentiated to relevant neural cell types

  • Develop organoid models to study FAM19A5 in 3D neural systems

  • Consider ex vivo slice cultures for studying FAM19A5 in preserved neural circuits

  • Employ optogenetic or chemogenetic approaches to manipulate FAM19A5-expressing cells

• Ethical and Practical Considerations:

  • Ensure proper informed consent and ethical approval

  • Account for post-mortem interval effects on protein integrity

  • Consider ante-mortem factors and comorbidities

  • Establish collaborations with brain banks and clinical centers

How should researchers design pharmacokinetic and pharmacodynamic studies for FAM19A5-targeting therapeutics?

Based on existing research with FAM19A5 antibodies, a comprehensive PK/PD study design should include:

• Pharmacokinetic Analysis:

  • Measure both plasma and brain concentrations following administration

  • Establish half-life in different compartments (plasma half-life ~6.8 days, brain half-life ~17.3 days reported)

  • Assess blood-brain barrier penetration kinetics

  • Determine optimal dosing intervals based on exposure profiles

• Pharmacodynamic Markers:

  • Develop assays to measure target engagement (bound vs. unbound FAM19A5)

  • Identify downstream biomarkers reflecting FAM19A5 modulation

  • Establish dose-response relationships for key biomarkers

  • Correlate PD markers with functional/behavioral outcomes

• Administration Protocols:

  • Compare different routes (IV, subcutaneous, intrathecal)

  • Establish minimum effective doses and regimens

  • Consider extended-release formulations based on half-life data

  • Evaluate potential for antibody-induced neutralizing responses

• Translational Considerations:

  • Allometric scaling from mouse models to human predictions

  • Species differences in FAM19A5 biology and therapeutic responses

  • Potential biomarkers for patient stratification

  • Integration with existing cognitive assessment protocols

How can researchers address the challenge of blood-brain barrier penetration when developing FAM19A5-targeting therapeutics?

When developing FAM19A5-targeting therapies, several strategies can enhance blood-brain barrier (BBB) penetration:

• Antibody Engineering Approaches:

  • Fc engineering to enhance receptor-mediated transcytosis

  • Reduced antibody size (Fab fragments, single-chain antibodies)

  • Bispecific antibodies targeting BBB transporters (e.g., transferrin receptor)

  • pH-dependent binding to enhance brain uptake and retention

• Alternative Delivery Systems:

  • Nanoparticle encapsulation of anti-FAM19A5 therapeutics

  • Exosome-based delivery systems

  • Cell-penetrating peptide conjugation

  • Intranasal delivery to access brain via olfactory routes

• Physical/Mechanical Methods:

  • Focused ultrasound for temporary BBB disruption

  • Convection-enhanced delivery for direct CNS administration

  • Intrathecal or intraventricular administration in severe cases

• PK/PD Optimization:

  • Maximize peripheral circulation time to enhance BBB penetration

  • Consider chronic low-dose regimens versus pulse high-dose approaches

  • Optimize molecular properties based on successful CNS-penetrant molecules

Current research indicates that systemic administration of FAM19A5 antibodies does achieve brain penetration, with detectable levels reached approximately 30 hours post-administration and a favorable brain half-life of 17.3 days . This suggests that with appropriate optimization, therapeutic levels can be achieved and maintained in the CNS.

What are the best approaches to resolve contradictory findings in FAM19A5 research across different disease models?

When confronted with contradictory results in FAM19A5 research:

• Standardization of Experimental Models:

  • Ensure consistent genetic backgrounds in animal models

  • Standardize age, sex, and environmental conditions

  • Define precise disease stages being examined

  • Use multiple independent models of the same disease

• Technical Validation:

  • Cross-validate findings using multiple methodologies

  • Ensure antibody specificity through knockout controls

  • Perform dose-response studies to identify potential biphasic effects

  • Consider the influence of experimental conditions (in vitro vs. in vivo)

• Contextual Analysis:

  • Evaluate role of FAM19A5 in different cell types/brain regions

  • Assess potential developmental versus adult functions

  • Consider compensatory mechanisms in chronic models

  • Examine genetic/environmental interactions

• Collaborative Approaches:

  • Establish multi-laboratory validation studies

  • Create standardized protocols and reagent sharing

  • Develop central repositories for FAM19A5-related data

  • Implement pre-registration of experimental designs

For example, the research shows that FAM19A5 levels have fluctuating effects in different neurological conditions , highlighting the need for careful contextual analysis and standardized approaches across studies.

How can advanced imaging techniques be optimized to study FAM19A5 distribution and function in the human brain?

Optimizing imaging approaches for FAM19A5 research requires:

• PET Imaging Development:

  • Develop FAM19A5-specific radioligands with high specificity and affinity

  • Optimize tracer kinetics for human brain imaging

  • Validate PET signals with post-mortem analyses

  • Combine with structural MRI for precise anatomical localization

• Advanced MRI Techniques:

  • Functional MRI to correlate FAM19A5 interventions with brain activity

  • Diffusion tensor imaging to assess white matter integrity

  • Magnetic resonance spectroscopy to measure related metabolites

  • Arterial spin labeling to assess regional cerebral blood flow changes

• Molecular Imaging in Animal Models:

  • Two-photon microscopy with fluorescent-tagged FAM19A5 antibodies

  • CLARITY or iDISCO techniques for whole-brain FAM19A5 mapping

  • Bioluminescence imaging of reporter constructs under FAM19A5 promoter

  • Correlative light and electron microscopy for subcellular localization

• Clinical Translation:

  • Development of imaging biomarkers for treatment monitoring

  • Correlation of imaging findings with fluid biomarkers

  • Longitudinal imaging to track disease progression

  • Integration with other molecular imaging approaches (e.g., amyloid PET)

What gene editing approaches show promise for studying FAM19A5 function in human neural cells?

Several gene editing strategies are applicable for FAM19A5 research:

• CRISPR-Cas9 Applications:

  • Complete knockout models to assess loss-of-function phenotypes

  • Knock-in of reporter genes to track expression patterns

  • Introduction of specific disease-associated mutations

  • Base editing for precise nucleotide modifications

• Inducible Systems:

  • Temporal control using Tet-On/Off systems

  • Cell-type-specific manipulation using Cre-loxP approaches

  • Rapamycin-inducible dimerization systems for protein function studies

  • Optogenetic or chemogenetic control of FAM19A5 expression

• Human Cell Models:

  • CRISPR editing in iPSC-derived neural cells

  • Isogenic cell line panels with controlled genetic backgrounds

  • Brain organoids with FAM19A5 modifications

  • High-throughput CRISPR screens to identify FAM19A5 interactors

• In Vivo Applications:

  • AAV-delivered CRISPR systems for regional brain manipulation

  • CRISPR base editing for introducing single nucleotide variants

  • Prime editing for precise genomic modifications

  • RNA editing approaches for transient functional studies

How might integrating multi-omics data advance our understanding of FAM19A5 in neurological disorders?

Multi-omics integration offers powerful approaches for FAM19A5 research:

• Comprehensive Data Types:

  • Genomics: Identify genetic variants affecting FAM19A5 expression or function

  • Transcriptomics: Map expression patterns across brain regions and cell types

  • Proteomics: Characterize FAM19A5 interactome and post-translational modifications

  • Metabolomics: Identify metabolic pathways influenced by FAM19A5

  • Epigenomics: Investigate regulatory mechanisms controlling FAM19A5 expression

• Integration Methodologies:

  • Network analysis to identify FAM19A5-centered functional modules

  • Machine learning approaches to identify pattern recognition across data types

  • Bayesian integrative models for causal relationship inference

  • Systems biology modeling of FAM19A5 pathways

• Single-Cell Applications:

  • Single-cell multi-omics to correlate FAM19A5 expression with cellular states

  • Spatial transcriptomics to map regional variation in human brain

  • Trajectory analysis to examine FAM19A5 dynamics during disease progression

  • Cell-type specific interactome analysis

• Translational Framework:

  • Patient stratification based on multi-omic signatures

  • Identification of companion biomarkers for FAM19A5-targeted therapies

  • Drug repurposing opportunities identified through network approaches

  • Personalized medicine approaches based on individual FAM19A5-related profiles

What are the emerging therapeutic approaches targeting FAM19A5 beyond traditional antibody-based methods?

Beyond antibody approaches, emerging therapeutic strategies include:

• Small Molecule Development:

  • High-throughput screening for FAM19A5 modulators

  • Structure-based drug design targeting FAM19A5-LRRC4B interaction

  • Allosteric modulators affecting FAM19A5 signaling

  • Brain-penetrant small molecule design principles

• RNA Therapeutics:

  • Antisense oligonucleotides targeting FAM19A5 mRNA

  • siRNA approaches for transient knockdown

  • mRNA therapeutics for transient overexpression in specific contexts

  • Long non-coding RNA modulators of FAM19A5 expression

• Gene Therapy:

  • AAV-mediated delivery of optimized FAM19A5 expression cassettes

  • CRISPR-based therapeutic editing of FAM19A5 or regulatory elements

  • Cell therapy with engineered FAM19A5-expressing cells

  • In vivo reprogramming approaches

• Combination Approaches:

  • Dual targeting of FAM19A5 and Aβ pathways

  • Synergistic approaches addressing multiple aspects of neurodegeneration

  • Stage-specific therapeutic strategies

  • Personalized approaches based on patient FAM19A5 profiles