Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases
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Changes in climbing fiber-Purkinje cell (CF-PC) synaptic connections have been found in the essential tremor (ET) cerebellum, and these changes are correlated with tremor severity. Whether these postmortem changes are specific to ET remains to be investigated. We assessed CF-PC synaptic pathology in the postmortem cerebellum across a range of degenerative movement disorders [10 Parkinson’s disease (PD) cases, 10 multiple system atrophy (MSA) cases, 10 spinocerebellar ataxia type 1 (SCA1) cases, and 20 ET cases] and 25 controls. We observed differences in terms of CF pathological features across these disorders. Specifically, PD cases and ET cases both had more CFs extending into the parallel fiber (PF) territory, but ET cases had more complex branching and increased length of CFs in the PF territory along with decreased CF synaptic density compared to PD cases. MSA cases and SCA1 cases had the most severely reduced CF synaptic density and a marked paucity of CFs extending into the PF territory. Furthermore, CFs in a subset of MSA cases formed collateral branches parallel to the PC layer, a feature not seen in other diagnostic groups. Using unsupervised cluster analysis, the cases and controls could all be categorized into four clusters based on the CF pathology and features of PC pathology, including counts of PCs and their axonal torpedoes. ET cases and PD cases co-segregated into two clusters, whereas SCA1 cases and MSA cases formed another cluster, separate from the control cluster. Interestingly, the presence of resting tremor seemed to be the clinical feature that separated the cases into the two ET-PD clusters. In conclusion, our study demonstrates that these degenerative movement disorders seem to differ with respect to the pattern of CF synaptic pathology they exhibit. It remains to be determined how these differences contribute to the clinical presentations of these diseases.
KeywordsEssential tremor Parkinson’s disease Spinocerebellar ataxia Multiple system atrophy Climbing fiber Purkinje cell
Dr. Arnulf H. Koeppen, Veterans Affairs Medical Center, Albany, New York, USA provided the rabbit polyclonal anti-VGluT2 antibody and the ten specimens of SCA1. We also thank the patients and families for the donation of brains and NYBB for processing of autopsy tissue.
Compliance with ethical standards
Dr. Kuo has received funding from the National Institutes of Health: NINDS #K08 NS083738 (principal investigator), and the Louis V. Gerstner Jr. Scholar Award, PD Foundation, and International ET Foundation, and NIEHS Pilot Grant ES009089 (principal investigator). Dr. Louis has received research support from the National Institutes of Health: NINDS #R01 NS042859 (principal investigator), NINDS #R01 NS39422 (principal investigator), NINDS #R01 NS086736 (principal investigator), NINDS #R01 NS073872 (principal investigator), NINDS #R01 NS085136 (principal investigator), and NINDS #R01 NS088257 (principal investigator). He has also received support from the Claire O’Neil ET Research Fund (Yale University). Dr. Faust has received funding from the National Institutes of Health: NINDS #R01 NS04289 (co-investigator), NINDS #R21 NS077094 (principal investigator), NINDS #R01 NS085136 (principal investigator), and NINDS #R01 NS088257 (principal investigator).
Conflict of interest
The authors report no conflicts of interest.
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