Selective Neuronal Vulnerability in Neurodegeneration

Selective vulnerability of brain regions and specific neural populations in neurodegeneration remains little understood. We hypothesize that pre-existing physiological differences in neurons and in surrounding glia across brain regions are likely to contribute to their selective vulnerability in disease. Spinocerebellar Ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by an abnormal expansion of polyglutamine (polyQ) repeats in the ATXN1 protein and characterized by early and severe cerebellar degeneration. Using histological approaches, we first demonstrated that the cerebellum of SCA1 mice does not undergo degeneration uniformly with worse Purkinje cell atrophy and gliosis in the posterior vermis, as seen in patients with SCA1. Using our novel region-specific dissection method and RNA sequencing, we identified genes and pathways across these three cerebellar cortical regions in wild-type and in SCA1 mice that may underlie different vulnerability. Finally, using fiber photometry we examined whether these histological and molecular pathologies result in different extent of neuronal dysfunctions in SCA1. This knowledge will increase our understanding of intraregional cellular, molecular and functional Purkinje cell differences in physiology and pathology.

Learning Objectives:

1. Discuss how inter- and intraregional heterogeneity of neurons and glia is a key characteristic of a healthy brain, while selective regional neuronal vulnerability and gliosis is a key feature of neurodegenerative diseases.

2. Discuss how molecular differences underlying inter-and intraregional heterogeneity of the brain likely contribute to selective vulnerability in brain disease.

3. Explain how larger cellular and molecular changes correlate with neuronal dysfunction in vulnerable regions, indicating that there is a threshold for dysfunction and/or compensatory changes in disease resistant regions.