TY - JOUR
T1 - Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss
AU - Benitez, Bruno A.
AU - Cairns, Nigel J.
AU - Schmidt, Robert E.
AU - Morris, John C.
AU - Norton, Joanne B.
AU - Cruchaga, Carlos
AU - Sands, Mark S.
N1 - Funding Information:
The authors especially want to thank the patients and their families, whose help and participation made this work possible. This work was funded in part by grants from the National Institutes of Health (NS043205 and NS084861 to MSS; P50 AG005681 and P01 AG003991 to JCM/NJC) and financial support from the Frye Family Foundation to MSS. This work was also supported by 2014 pilot funding from the Hope Center for Neurological Disorders and the Danforth Foundation Challenge at Washington University to BAB and CC. We thank Dr. Shonali Midha who provided editing and insightful discussion of the manuscript.
PY - 2015/11/26
Y1 - 2015/11/26
N2 - 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 (CSPα), 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 CSPα 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 CSPα 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 CSPα mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction.
AB - 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 (CSPα), 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 CSPα 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 CSPα 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 CSPα mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction.
UR - http://www.scopus.com/inward/record.url?scp=84966339419&partnerID=8YFLogxK
U2 - 10.1186/s40478-015-0256-5
DO - 10.1186/s40478-015-0256-5
M3 - Article
C2 - 26610600
AN - SCOPUS:84966339419
SN - 2051-5960
VL - 3
SP - 73
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
ER -