Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntington's disease

PLoS One. 2020 Aug 17;15(8):e0233820. doi: 10.1371/journal.pone.0233820. eCollection 2020.


Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible means of exploring the pathobiology of Huntington's disease (HD) in vivo. The endo-lysosomal/autophagy system is dysfunctional in HD, potentially contributing to disease pathogenesis and representing a potential target for therapeutic intervention. Several endo-lysosomal proteins have shown promise as biomarkers in other neurodegenerative diseases; however, they have yet to be fully explored in HD. We performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 healthy controls. Using generalised linear models controlling for age and CAG, none of the 18 proteins measured displayed significant differences in concentration between HD patients and controls. This was affirmed by principal component analysis, in which no significant difference across disease stage was found in any of the three components representing lysosomal hydrolases, binding/transfer proteins and innate immune system/peripheral proteins. However, several proteins were associated with measures of disease severity and cognition: most notably amyloid precursor protein, which displayed strong correlations with composite Unified Huntington's Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We conclude that although endo-lysosomal proteins are unlikely to have value as disease state CSF biomarkers for Huntington's disease, several proteins demonstrate associations with clinical severity, thus warranting further, targeted exploration and validation in larger, longitudinal samples.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyloid beta-Protein Precursor / cerebrospinal fluid
  • Biomarkers / cerebrospinal fluid
  • Case-Control Studies
  • Cerebrospinal Fluid Proteins / metabolism*
  • Cognition
  • Cross-Sectional Studies
  • Disease Progression
  • Endosomes / metabolism
  • Female
  • G(M2) Activator Protein / cerebrospinal fluid
  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease / cerebrospinal fluid*
  • Huntington Disease / genetics
  • Huntington Disease / psychology
  • Linear Models
  • Longitudinal Studies
  • Lysosomal Membrane Proteins / cerebrospinal fluid
  • Lysosomal-Associated Membrane Protein 2 / cerebrospinal fluid
  • Male
  • Mass Spectrometry / methods
  • Middle Aged
  • Principal Component Analysis
  • Prospective Studies
  • Proteins / metabolism
  • Trinucleotide Repeat Expansion


  • Amyloid beta-Protein Precursor
  • Biomarkers
  • Cerebrospinal Fluid Proteins
  • G(M2) Activator Protein
  • HTT protein, human
  • Huntingtin Protein
  • LAMP1 protein, human
  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2
  • Lysosomal Membrane Proteins
  • Proteins
  • lysosomal proteins