The necessity of understanding causes of neurodegenerative diseases and developing potential treatments is increasing as life expectancy is extending. Parry disease (CLN4B) is an autosomal dominant form of Neuronal Ceroid Lipofuscinosis (NCL) with adult onset (ANCL). NCL comprises a group of inherited neurodegenerative diseases of children and occasionally adults that lead to physical deterioration, seizures, blindness, dementia, and premature death. NCL is morphologically characterized by degeneration of the cortex and cerebellum, and by lysosomal accumulations of lipofuscin. Parry disease (CLN4B) is caused by dominant lethal mutations in the DNAJC5 gene encoding CSP?, a well-studied synaptic vesicle protein that is neuroprotective and required to maintain synaptic function. Little is known about disease etiology besides biochemical evidence that the disease-causing dominant mutations in CSP? trigger the formation of large protein aggregates that contain mutant but also normal CSP?. However, whether these aggregates cause neurotoxic gain- and/or loss-of-function effects or, alternatively, are neuroprotective is no known. To gain a comprehensive understanding of mechanisms underlying Parry Disease, we face three challenges: The first is to systematically identify the nature(s) of the toxicity triggeing neuronal failure and neurodegeneration. The second is to identify the impaired molecular and cellular signaling pathways that are impaired by the toxic substrate or can counteract its effects. The third is to understand how the various signaling pathways interact with and feedback on each other to maintain homeostasis and prevent neuronal failure and neurodegeneration. We propose to establish the first animal model for Parry Disease by expressing disease-causing human CSP? in Drosophila. The fly is well suited to dissect the likely complex genetic nature of the disease since the neuroprotective and synaptic functions of fly and mouse CSP are well conserved, loss- and gain of function mutants of fly CSP are well studied, and numerous other sophisticated genetic tools aiding the analysis are available. To gain critical mechanistic insight into the etiology of Parry Disease, we suggest a rigorous and comprehensive analysis dissecting the genetic nature of the dominant mutations, the affected neuronal signaling pathways, and a genome-wide unbiased genetic identification of genes that positively or negatively contribute to the disease. Uncovering molecules and signaling pathways that are either impaired or able to counteract the effects of the disease-causing mutations in CSP will significantly expand our understanding of disease etiology and may accelerate the development of new therapeutic concepts treating Parry Disease.
This project aims to establish a Drosophila model of Parry Disease/CLN4B, an autosomal dominant neurodegenerative disease with lysosomal storage pathology that is caused by dominant mutations in the synaptic vesicle protein CSP?, which has no link to lysosomal function. Currently, there is no animal model explaining the pathology and neuronal loss of CLN4B. This proposal seeks to identify the primary cellular and molecular events leading to neuronal failure and the likely complex genetic nature of the mutations.
| Coyne, Alyssa N; Lorenzini, Ileana; Chou, Ching-Chieh et al. (2017) Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS. Cell Rep 21:110-125 |
