Role of Alterations in Protein Kinase p38γ in the Pathogenesis of the Synaptic Pathology in Dementia With Lewy Bodies and α-Synuclein Transgenic Models

Progressive accumulation of the pre-synaptic protein alpha-synuclein (alpha-syn) has been strongly associated with the pathogenesis of neurodegenerative disorders of the aging population such as Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. While the precise mechanisms are not fully understood, alterations in kinase pathways including that of mitogen activated protein kinase (MAPK) p38 have been proposed to play a role. In AD, p38 alpha activation has been linked to neuro-inflammation while alterations in p38 gamma have been associated with tau phosphorylation. Although p38 has been studied in AD, less is known about its role in DLB/PD and other alpha-synucleinopathies. For this purpose, we investigated the expression of the p38 family in brains from alpha-syn overexpressing transgenic mice (alpha-syn Tg: Line 61) and patients with DLB/PD. Immunohistochemical analysis revealed that in healthy human controls and non-Tg mice, p38 alpha associated with neurons and astroglial cells and p38 gamma localized to pre-synaptic terminals. In DLB and alpha-syn Tg brains, however, p38 alpha levels were increased in astroglial cells while p38 gamma immunostaining was redistributed from the synaptic terminals to the neuronal cell bodies. Double immunolabeling further showed that p38 gamma colocalized with alpha-syn aggregates in DLB patients, and immunoblot and qPCR analysis confirmed the increased levels of p38 alpha and p38 gamma. alpha 1-syntrophin, a synaptic target of p38 gamma, was present in the neuropil and some neuronal cell bodies in human controls and non-Tg mice. In DLB and and Tg mice, however, alpha 1-syntrophin was decreased in the neuropil and instead colocalized with alpha-syn in intra-neuronal inclusions. In agreement with these findings, in vitro studies showed that alpha-syn co-immunoprecipitates with p38 gamma, but not p38 alpha. These results suggest that alpha-syn might interfere with the p38 gamma pathway and play a role in the mechanisms of synaptic dysfunction in DLB/PD.