期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 3, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s40478-015-0256-5
关键词
Neuronal ceroid lipofuscinosis; Cysteine string protein alpha; Synaptic loss; Neurodegenerative disease; Lysosome DNAJC5
资金
- NIA NIH HHS [P01 AG003991, P50 AG005681] Funding Source: Medline
- NINDS NIH HHS [R01 NS043205, NS043205, R01 NS084861, NS084861, R56 NS043205] Funding Source: Medline
Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the DNAJC5 gene. DNAJC5 encodes Cysteine String Protein-alpha (CSPa), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on the intracellular accumulation of ceroid material. Here, we report for the first time the pathological findings of a patient in a clinically early stage of disease, which exhibits the typical neuronal intracellular ceroid accumulation and incipient neuroinflammation but no signs of brain atrophy, neurodegeneration or massive synaptic loss. Interestingly, we found minimal or no apparent reductions in CSPa or synaptophysin in the neuropil. In contrast, brain homogenates from terminal AD-ANCL patients exhibit significant reductions in SNARE-complex forming presynaptic protein levels, including a significant reduction in CSPa and SNAP-25. Frozen samples for the biochemical analyses of synaptic proteins were not available for the early stage AD-ANLC patient. These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of CSPa mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction.
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