Neurexin1 level in Huntington’s Disease and decreased Neurexin1 in disease progression

Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by the presence of abnormally expanded polyglutamine tracts in huntingtin protein (HTT). Mutant HTT disrupts synaptic transmission and plasticity, particularly in the striatum and cortex, leading to early dysfunctions, such as altered neurotransmitter release, impaired synaptic vesicle recycling, and disrupted postsynaptic receptor function. Synaptic loss precedes neuronal degeneration and contributes to disease progression. Neurexin1 (NRXN1), a synaptic cell adhesion molecule primarily located in the presynaptic membrane, plays a crucial role in maintaining synaptic integrity. The present study investigated the role of NRXN1 in HD. This study researched whether the changed level has been related to expanded polyQ stretch and disease progression. Here, we report a reduction in NRXN1 levels in post-symptomatic HD mice and in neuronal cells expressing abnormally expanded polyQ tracts. Mutant HTT was found to decrease NRXN1 levels while increasing LAMP2A levels, which promotes lysosomal degradation of NRXN1. In HD cells expressing Q111, downregulated LAMP2A restored NRXN1 levels and maintained cell proliferation compared with cells expressing Q7. These findings suggest that NRXN1 is regulated by LAMP2A-mediated way and that decreased NRXN1 levels are associated with symptomatic progression and neuronal cell loss in HD.