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Related Experiment Videos

An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a

Yasir H Qureshi1, Vivek M Patel1, Diego E Berman1,2

  • 1The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.

Molecular and Cellular Biology
|July 25, 2018
PubMed
Summary

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A rare CLN5 gene variant linked to Alzheimer's disease (AD) disrupts protein transport, affecting amyloid precursor protein (APP) processing and retromer pathway function in brain cells.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Alzheimer's disease (AD) is a neurodegenerative disorder with complex genetic underpinnings.
  • The retromer complex is crucial for intracellular trafficking and has been implicated in AD pathogenesis.
  • Neuronal ceroid lipofuscinosis (NCL) genes, including CLN5, are linked to retromer function.

Purpose of the Study:

  • To investigate the role of NCL genes (CLN3, CLN5, CTSD) in AD pathogenesis within multiplex families.
  • To identify genetic variants in these genes associated with Alzheimer's disease.
  • To elucidate the cellular and molecular consequences of identified variants on protein trafficking and AD-related pathways.

Main Methods:

  • Whole-exome sequencing in multiplex Alzheimer's disease families.
Keywords:
Alzheimer's diseaseCLN5NCLendosomesretromer

Related Experiment Videos

  • Segregation analysis of identified variants.
  • Functional studies of the CLN5 variant, including protein expression, localization, and glycosylation analysis.
  • Assessment of cathepsin D processing and amyloid precursor protein (APP) levels.

    • Main Results:

    • A missense variant (c.A959G, p.Asn320Ser) in the CLN5 gene was identified and segregated with AD in affected families.
    • This CLN5 variant leads to protein misfolding and endoplasmic reticulum retention, impairing delivery to the endolysosomal pathway.
    • The variant reduces cathepsin D processing and decreases full-length APP levels, indicating a defect in retromer-dependent trafficking.

    Conclusions:

    • The identified CLN5 variant is associated with Alzheimer's disease and disrupts normal protein trafficking.
    • This finding highlights a potential role for CLN5 dysfunction and impaired retromer activity in AD pathogenesis.
    • Further research into CLN5 and retromer pathways may offer new therapeutic targets for Alzheimer's disease.