␣-synucleinopathy ͉ mass spectrometry ͉ proteolysis ͉ Lewy body P arkinson's disease (PD) is a common progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of substantia nigra and the presence of the fibrillar cytoplasmic aggregates of ␣-synuclein (␣-Syn) in multiple brain regions (1, 2). Mutations in the ␣-Syn gene (3-7) and the abnormal aggregation of ␣-Syn are implicated in the pathogenesis of PD, and other related diseases are classified as ␣-synucleinopathies (1, 8-10). ␣-Syn is a highly conserved protein of 140 amino acids that is predominantly expressed in neurons, particularly in presynaptic terminals (11), and may have a role in synaptic plasticity and modulation of dopaminergic neurotransmission (11).Although the bulk of previous studies focused on the aggregation and the biology of the full-length ␣-Syn (␣-SynFL) (12, 13), the conspicuous presence of lower molecular mass ␣-Syn species in ␣-Syn aggregates (14, 15), and the enhanced in vitro fibril assembly of recombinant C-terminally truncated ␣-Syn (16, 17) suggests that the low-molecular mass ␣-Syn species may be of pathogenic significance. However, because postpathogenic and͞or postmortem processes could potentially generate a variety of ␣-Syn species, the significance of low-molecular mass ␣-Syn species to the development of ␣-synucleinopathy is uncertain.Herein, we demonstrate that C-terminally truncated lowmolecular mass ␣-Syn species (␣-Syn⌬C) with aggregationpromoting properties are normally generated in vivo. The expression of familial PD (FPD)-linked mutant human (Hu) ␣-Syn is associated with the higher cellular accumulation of ␣-Syn⌬C. Moreover, human cases with ␣-Syn lesions show preferential accumulation of ␣-Syn⌬C in aggregates and higher relative levels of soluble ␣-Syn⌬C. Our findings show that ␣-Syn⌬Cs are not an artifact of postpathologic processes and are likely to participate in the disease-linked aggregation of ␣-Syn. Materials and MethodsAdditional details are provided in Supporting Materials and Methods, which is published as supporting information on the PNAS web site.
Real-time monitoring of stimulated dopamine release in mice with different ␣-synuclein expression was used to study the role of ␣-synuclein in presynaptic dopamine recruitment. Repeated electrical stimulations of ascending dopaminergic pathways decreased the capacity of the readily releasable pool (RRP) and temporarily increased its refilling rate, significantly slowing the rate of dopamine decline in mice with normally expressed ␣-synuclein. Mice with ␣-synuclein null mutation demonstrated a permanent increase of the refilling rate. This increase maintained stable dopamine release during stimulation (which induced dopamine decline in other animals) and served as an adaptation to altered dopamine compartmentalization. Mice without ␣-synuclein and with overexpression of human A30P mutated ␣-synuclein had a lower capacity of the dopamine storage pool than other animals. Reducing capacity of the storage pool in transgenic A30P mice led to paradoxical effects of L-dopa, which elevated dopamine release in response to single stimulation but decreased the refilling rate of the RRP.
Intracellular inclusions containing a-synuclein (aSN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of aSN, this study compared the levels, solubility and molecular weight species of aSN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble aSN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had signi®cantly higher levels of aSN in the detergent-soluble fraction of brain samples from pons and white matter but detergent-insoluble aSN was not detected. There was an inverse correlation between buffered salinesoluble and detergent-soluble levels of aSN in individual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of aSN between grey and white matter in disease may result from different processing of aSN in neurons compared with oligodendrocytes. Highly insoluble aSN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of aSN are involved in the pathogenesis of other aSN-related diseases.
Exercise therapy with walking training improved gait function irrespective of the method used, but the time and effort required to achieve the results favour the gait trainer exercise. Early intensive gait training resulted in better walking ability than did conventional treatment.
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