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

Abstract

25Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible 26 means of exploring the pathobiology of Huntington's disease (HD) in vivo. The endo-27 lysosomal/autophagy system is dysfunctional in HD, potentially contributing to 28 disease pathogenesis and representing a potential target for therapeutic intervention. 29Several endo-lysosomal proteins have shown promise as biomarkers in other 30 neurodegenerative diseases; however, they have yet to be fully explored in HD. We 31 performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of 32 multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 33 healthy controls. Using generalised linear models controlling for age and CAG, none 34 of the 18 proteins measured displayed significant differences in concentration 35 between HD patients and controls. This was affirmed by principal component 36 analysis, in which no significant difference across disease stage was found in any of 37 the three components representing lysosomal hydrolases, binding/transfer proteins 38 and innate immune system/peripheral proteins. However, several proteins were 39 associated with measures of disease severity and cognition: most notably amyloid 40 precursor protein, which displayed strong correlations with composite Unified 41 Huntington's Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS 42 Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We 43 conclude that although endo-lysosomal proteins are unlikely to have value as 44 disease state CSF biomarkers for Huntington's disease, several proteins 45 demonstrate associations with clinical severity, thus warranting further, targeted 46 exploration and validation in larger, longitudinal samples. 49 Huntington's disease (HD) is an autosomal dominant, neurodegenerative disease 50 characterised by progressive motor, psychiatric and cognitive dysfunction [1]. An51 extended polyglutamine tract (polyQ) in the ubiquitously-expressed Huntingtin 52 protein (HTT), results in the production of a mutated, pathogenic product (mHTT) 53 which accumulates intracellularly causing toxicity and neuronal death [2,3]. 54 Neuronal survival is dependent, among other things, on intracellular surveillance 55 mechanisms including autophagy, a lysosomal pathway that serves to eliminate toxic 56 substances via two mechanisms: macroautophagy and chaperone-mediated 57 autophagy (CMA) [4,5]. Both of these are disrupted in neurodegenerative diseases 58 including Parkinson's disease (PD), Alzheimer's disease (AD) and polyQ disorders 59 [6-12], potentially resulting in autophagic dysfunction and exacerbation of the 60 neurodegenerative process [13].61Lysosomal-associated membrane protein-2 (LAMP2) has pivotal roles in autophagy 62 including translocation of cargo into the lumen and as a receptor in CMA [14,15]. 63LAMP2 gene expression levels and total levels of LAMP2 protein have been shown 64 to be reduced and increased in PD and AD respectively [16][17][18][19]. Additionally...

Neurofilament Light Protein as a Potential Blood Biomarker for Huntington's Disease in Children

“…We pooled plasma NfL measurement data from the Kids‐HD/JHD with adult participants from HD‐CSF 6,8,12 to evaluate the nonlinear plasma NfL dynamics by disease burden score (DBS = age × [CAG‐35.5]) 14 using LMER models. A two degrees‐of‐freedom test was performed for the joint significance of the two‐spline transformation of DBS.…”

Intracortical surface‐based MR diffusivity to investigate neurologic and psychiatric disorders: a review

“…This reinforces the specific role of neuroinflamation in AD but not in other neurodegenerative diseases. In addition, this result contributes to clarify ongoing controversies on the role of beta‐amyloid deposition in early PD and HD 20–25 …”

“…In addition, this result contributes to clarify ongoing controversies on the role of beta-amyloid deposition in early PD and HD. [20][21][22][23][24][25] F I G U R E 2 Schematic representation of the biological interpretation of intracortical mean diffusivity (MD) changes. In normal conditions, the diffusion of water (blue lines) within the cerebral cortex is restricted by local neuronal density (purple cells).…”

Cerebrospinal fluid amyloid beta and glial fibrillary acidic protein concentrations in Huntington’s disease

“…A recent study demonstrated an association between lower levels of CSF amyloid precursor protein (APP) and worse clinical phenotype and lower cognitive performance in HD patients [52], the strongest relationship observed with composite UHDRS score. APP is a transmembrane protein with multiple physiological functions, including regulating brain iron homeostasis [53], and it is cleaved by beta- and gamma-secretase to form Aβ peptides [54, 55].…”