Cell Death Mechanisms in Multiple System Atrophy

Abstract

The presence and distribution of apoptotic cell death in multiple system atrophy (MSA) and morphologically related diseases were investigated by means of a modified terminal deoxynucleotidyl transferase-mediated nick end labeling method, comparing their distribution with that of glial cytoplasmic inclusions, immunohistochemically demonstrated bcl-2 protein, bax protein, CD95, TNFalpha, and p53-protein expression, as well as activated microglia. Apoptosis occurred almost exclusively in oligodendrocytes in multiple system atrophy and its general distribution was comparable to the already known oligodendroglial pathology in this disorder. Additionally, in about a quarter of glial cytoplasmic inclusions, there was upregulation of bcl-2-protein and coexpression with ubiquitin, suggesting a final attempt of involved cells to counteract apoptotic cell death. Bax protein was also demonstrated in oligodendroglial cells. A significant neuronal apoptosis was not observed in MSA; these cells might be destroyed secondarily to oligodendroglial apoptosis by necrosis or other forms of programmed cell death. These results emphasize the central role of oligodendroglial pathology in multiple system atrophy, making this disease unique among neurodegenerative diseases.

Mice expressing the α1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

“…We previously reported higher TUNEL staining in the transgenic brains (Zuscik et al 2000) and the transgenic nuclei do appear apoptotic (Fig. 3b), which is consistent with suggestions in the literature that MSA brains undergo a significant amount of apoptosis (Probst-Cousin et al 1998).…”

Cell death mechanisms in neurodegeneration

“…Lewy bodies, the morphologic markers of PD, are consistently negative [24]. In DLB, similar controversial findings have been reported [21,24,48] ARPs and activated caspase 3 were not seen in neurons but only in microglia and oligodendroglia with α-synuclein/ ubiquitin positive GCIs [25,39]. Distinct cytoplasmic expression of Bcl-2, often with co-expression of α-synuclein in oligodendroglia, that are usually Bcl-2 negative, suggests a final repair mechanism in sublethally damaged cells to avoid cell death via apoptosis, by upregulation of this antiapoptotic protein [25].…”

“…These include cell shrinkage, chromatic condensation, DNA fragmentation, and increased expression of both proapototic (c-Jun, c-Fax, Bax, p53, APO-1/Fas-CD95, Fas, Fas-L, caspase 8 and 9, activated caspase 3, tumor necrosis factor R1/p55), and antiapoptotic proteins (Bcl-2, Bcl-x), or DNA repair enzymes, such as Ref-1 and the co-expressed GADD45 [13, 16,20,[23][24][25][26][27][28][29][30][31][32][33][34][35][36]. However, other groups have observed little or no evidence of apoptotic neuronal cell death associated with neurodegenerative diseases [24,[37][38][39][40][41][42][43]. These studies have relied on the presence of Table 2).…”

Neurological and Neurodegenerative Alterations in a Transgenic Mouse Model Expressing Human α-Synuclein under Oligodendrocyte Promoter: Implications for Multiple System Atrophy

“…MSA is a sporadic, progressive neurological disorder characterized by parkinsonism, cerebellar dysfunction, autonomic impairment and pyramidal signs (Graham and Oppenheimer, 1969;Gilman et al, 1999;Shults and Gilman, 2003), and ␣-syn-immunoreactive glial cytoplasmic inclusions (GCIs) in oligodendrocytes (Lantos and Papp, 1994;Lantos, 1998;Wakabayashi et al, 1998a;Dickson et al, 1999;Gai et al, 1999;Duda et al, 2000;Dickson, 2001;Goedert, 2001) in several brain regions (Wenning and Jellinger, 2005). These inclusions are accompanied by neuronal loss, astrogliosis, and demyelination (Probst-Cousin et al, 1998;Wenning and Jellinger, 2005).…”