Molecular Biology

The discovery of GCIs in MSA brains firmly established glial pathology as a biological hallmark of this disorder, akin to the LB of PD. GCIs are argyrophilic and half moon, oval, or conical in shape (Lantos, 1998; Papp et al., 1989). They consist of 20 to 30 nm diameter filaments and contain the classical cytoskeletal antigens, ubiquitin and tau (Lantos, 1998; Cairns et al., 1997a). Furthermore, a-synuclein, a presynaptic protein which is affected by point mutations in some families with autosomal dominant PD (Goedert and Spillantini, 1998) and which is present in LBs (Spillantini et al., 1997), has also been observed in both neuronal and glial cytoplasmic inclusions (Wakabayashi et al., 1998c; Arima et al., 1998; Tu et al., 1998) in brains of patients with MSA. The accumulation of a-synuclein into filamentous inclusions appears to play a mechanistic role in the patho-genesis of several a-synucleinopathies including PD, dementia with LBs, Down syndrome, familial AD, sporadic AD, MSA, and other synucleinopathies (Trojanowski et al., 2002). The a-synuclein accumulation in these inclusions appears to precede their ubiquitination, because a-synuclein antibodies detect a greater number of inclusions than ubiq-uitin antibodies (Gai et al., 1998). Importantly, a-synuclein, but not ubiquitin, antibodies also reveal numerous degenerating neurites in the white matter of MSA cases (Gai et al., 1998). This suggests that an as yet unrecognized degree of pathology may be present in the axons of MSA cases, although whether neuronal/axonal a-synuclein pathology precedes glial a-synuclein pathology has not been examined.

V. PATHOGENESIS/MECHANISM OF DISEASE

The a-synuclein pathway appears to be the key pathway to selective loss of glia and neurons in MSA. The differential distribution of a-synuclein deposits and associated neuronal pathology (SND, OPCA, and spinal cord) suggests variability of pathogenetic mechanisms underlying the multifaceted disease process of MSA.

MSA, as reflected in its current definition, is regarded as a sporadic disease (Wenning et al., 1993) and no confirmed familial cases of MSA have yet been described. Even so, it is conceivable that genetic factors may play a role in the etiology of the disease. However, initial screening studies for candidate genes revealed no risk factors (Bandmann et al.,

1997; Nicholl et al., 1999). Other recent studies have further looked for polymorphisms or mutations in candidate genes, which may predispose an individual toward developing MSA. The apolipoprotein e4 allele is not over-represented in MSA when compared with controls, and there have been conflicting reports of the association of a cytochrome P-450-2D6 polymorphism with MSA (Iwahashi et al., 1995; Bandmann et al., 1995; Cairns et al., 1997b).

The pathogenetic role of a-synuclein is still unclear. Inactivation of the a-synuclein gene by homologous recombination did not lead to a severe neurological phenotype (Abeliovich et al., 2000). Therefore, loss of function of the a-synuclein protein is unlikely to account for its role in neurodegeneration. Mice lacking a-synuclein were found to show increased release of striatal dopamine, indicating that this protein could function as an activity-dependent, negative regulator of neurotransmission in the striatum. While there is strong evidence that a-synuclein participates in the pathogenesis of some types of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998), no mutations have been found in the entire coding region of the a-synuclein gene in MSA (Ozawa et al., 1999) or in sporadic forms of PD (El-Agnaf et al., 1998). However, polymorphisms in the a-synuclein gene have been identified in PD (Kruger et al., 1999). They may also increase the risk of developing MSA by promoting a-synuclein protein aggregation. Polymorphisms in codons 1 to 39 of the a-synuclein gene, a domain related to interaction with synphilin-1, or indeed polymorphisms in the synphilin-1 gene itself, or in the genes of other protein-interacting partners of a-synu-clein, may also need to be considered in the pathogenesis of MSA (Engelender et al., 1999). The number of a-synuclein protein-interacting partners has expanded to include 14-3-3 protein chaperones, protein kinase C, extracellular regulated kinase, and BAD, a molecule that regulates cell death (Ostrerova et al., 1999). Nevertheless, association studies with genetic polymorphisms for a-synuclein have so far been negative in MSA (Bandmann, 1997; Morris et al., 2000).

Gilman et al. (1996) have reported an MSA-like phenotype including GCI like (a-synuclein negative) inclusions in one SCA1 (spinocerebellar ataxia type 1) family. Other SCA mutations (except for SCA-2 [Bösch et al., 2002a]) have not been reported to present with MSA-like features (Schöls et al., 2000; Ranum et al., 1995; Silveira et al., 1996; Leggo et al., 1997; Futamura et al., 1998; Moseley et al., 1998). Conversely, the majority of MSA-C patients do not appear to have expanded SCA1 and SCA3 alleles (Bandmann et al., 1997). Indeed, MSA-C appears to be a frequent form of sporadic cerebellar ataxia of late onset. Nearly thirty percent of sporadic adult-onset ataxia patients suffer from MSA (Abele et al., 2002). This finding corresponds well to data of a study of sporadic OPCA patients who were followed up for ten years (Gilman et al., 2000). Within this period, seventeen out of fifty-one patients developed autonomic failure or Parkinsonism, indicating a diagnosis of MSA.

To summarize, the up-to-date knowledge about the role of a-synuclein and its aggregation in neurodegenerative disorders remains unclear. It is not yet elucidated how the expression and aggregation of a-synuclein in glial cells affects their biology as well as the glia-neuron interactions, which might be a critical step in the pathogenesis of a-synucleinopathies. Whether environmental factors influence a-synuclein aggregation and the survival of glial and neuronal cells remains unknown as well.

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