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PYK2 in the dorsal striatum of Huntington's disease R6/2 mouse model
Omar Al Massadi1, Mélody Labarchède2, Benoit de Pins1
1Inserm UMR-S 1270, Paris 75005, France; Sorbonne Université, Faculty of Sciences and Engineering, Paris 75005, France; Institut du Fer à Moulin, 17 rue du Fer à Moulin, Paris 75005, France.
Insights
Huntington's disease (HD) involves decreased PYK2 protein in the striatum. Viral PYK2 expression in the striatum of HD mice showed minor improvements, suggesting limited therapeutic potential for this specific intervention.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by HTT gene mutations.
- Molecular alterations, including transcriptional defects, contribute to HD pathophysiology.
- Previous studies indicated reduced PYK2 protein in the hippocampus of HD patients and models, with viral PYK2 improving hippocampal function.
Purpose of the Study:
- To investigate the role of PYK2 in the striatum, a brain region significantly affected in HD.
- To determine if restoring PYK2 levels in the striatum of HD mouse models could ameliorate disease phenotypes.
Main Methods:
- Assessed PYK2 mRNA and protein levels in the striatum and hippocampus of R6/2 HD mice and human HD patients.
- Utilized adeno-associated virus (AAV) vectors to express PYK2 in the dorsal striatum of R6/2 mice.
- Evaluated motor functions, including body weight, clasping, rotarod performance, and motor activity.
Main Results:
- PYK2 mRNA and protein levels were decreased in the striatum of R6/2 mice and HD patients.
- PYK2 knockout alone did not induce HD-like motor symptoms.
- AAV-mediated PYK2 expression in the striatum showed minimal improvement in R6/2 mouse phenotypes, with some effects potentially linked to expression in cholinergic interneurons.
Conclusions:
- PYK2 is downregulated in the striatum of HD patients and models, similar to the hippocampus.
- Unlike the hippocampus, restoring striatal PYK2 levels via viral vectors had a limited impact on the R6/2 mouse model's striatal phenotype.
Abstract:
Huntington's disease (HD) is a devastating disease due to autosomal dominant mutation in the HTT gene. Its pathophysiology involves multiple molecular alterations including transcriptional defects. We previously showed that in HD patients and mouse model, the protein levels of the non-receptor tyrosine kinase PYK2 were decreased in the hippocampus and that viral expression of PYK2 improved the hippocampal phenotype. Here, we investigated the possible contribution of PYK2 in the striatum, a brain region particularly altered in HD. PYK2 mRNA levels were decreased in the striatum and hippocampus of R6/2 mice, a severe HD model. Striatal PYK2 protein levels were also decreased in R6/2 mice and human patients. PYK2 knockout by itself did not result in motor symptoms observed in HD mouse models. We examined whether PYK2 deficiency participated in the R6/2 mice phenotype by expressing PYK2 in their dorsal striatum using AAV vectors. With an AAV1/Camk2a promoter, we did not observe significant improvement of body weight, clasping, motor activity and coordination (rotarod) alterations observed in R6/2 mice. With an AAV9/SYN1 promoter we found a slightly higher body weight and a trend to better rotarod performance. Both viruses similarly transduced striatal projection neurons and somatostatin-positive interneurons but only AAV9/SYN1 led to PYK2 expression in cholinergic and parvalbumin-positive interneurons. Expression of PYK2 in cholinergic interneurons may contribute to the slight effects observed. We conclude that PYK2 mRNA and protein levels are decreased in the striatum as in hippocampus of HD patients and mouse models. However, in contrast to hippocampus, striatal viral expression of PYK2 has only a minor effect on the R6/2 model striatal phenotype.
