Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK.
Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo.
J Neurosci. 2012 Mar 7;32(10):3301-5.
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This paper examines toxic α-synuclein in the endoplasmic reticulum (ER) of a mouse model of synucleinopathy and in brain tissue from people with Parkinson’s disease using antibodies against α-synuclein oligomers and phosphorylated forms. Determining the nature of the toxic protein species in neurodegenerative diseases and the mechanism by which they function have been a research focus over recent years. Starting with analysis of which form of amyloid-β (Aβ) is pathology-causing in Alzheimer’s disease (monomers, oligomers, or plaques), the field has now moved on to ask similar questions of other pathological proteins, including α-synuclein in Lewy body diseases. The detection of toxic α-synuclein oligomers in both a mouse model of synucleinopathy and human Parkinson’s disease brains is an important step on the pathway to new treatments and biomarker discoveries. Further, a pathological link between this mouse model and human disease validates this as a research tool for future use.
How α-synuclein causes proteasome and lysosome/autophagy dysfunction remains unclear. Therefore, identifying the location and nature of toxic α-synuclein within cells is an important step in resolving its role in neurodegeneration. Furthermore, identifying the toxic form of the protein is important for developing targeted drugs with minimal impact on other forms of the protein, and for identifying if treatments are disease modifying or symptomatic. Recently, Santos et al. showed a correlation between oligomeric Aβ in the cerebrospinal fluid of people with Alzheimer’s disease and cognition—an important step in identifying a biomarker of disease progression. Progress in identifying the most toxic α-synuclein oligomers will allow for improved focus of ELISAs for finding biomarkers for disease progression.
Santos AN, Ewers M, Minthon L, Simm A, Silber RE, Blennow K, Prvulovic D, Hansson O, Hampel H.
Amyloid-β oligomers in cerebrospinal fluid are associated with cognitive decline in patients with Alzheimer's disease.
J Alzheimers Dis. 2012;29(1):171-6.
This is an interesting paper, indicating a marked elevation in the levels of various truncated and multimeric α-synuclein species in the endoplasmic reticulum (ER) from α-synuclein transgenic mice and PD patients. In mice, aggregated α-synuclein species appear in the ER as the animals become symptomatic. However, the authors do not really provide any data that the toxicity is mediated by the oligomers per se. The evidence for that conclusion is only indirect, as the accumulated protein is immunoreactive with A11, an oligomer-selective antibody that was found to inhibit oligomer-induced toxicity in vitro. Another uncertainty relates to the fact that both A11 and a prefibrillar/fibril-selective antibody, FILA-1, were used solely for dot-blot analyses. Identification of soluble intermediates is likely to be less reliable in analyses on solid-phases as compared to assessments in solution, e.g., ELISA. Anyhow, the accumulation of prefibrillar/fibrillar α-synuclein species in the ER seems to be of pathogenic relevance also for human disease, as a robust increase in both A11 and FILA-1 reactivity could be demonstrated in a number of Parkinson's disease brains. Finally, the effect of orally administered salubrinal, an inhibitor of eIF2-dephosphorylation, was shown to reduce ER levels of prefibrillar/fibrillar α-synuclein in mice. Interestingly, the pharmacologically induced decrease of presumably toxic α-synuclein species was accompanied by an attenuation of motor dysfunction—as is reported in a parallel-published paper from the same group. This treatment paradigm provides additional evidence that pathological α-synuclein should be an attractive target for future pharmacological intervention in Parkinson’s disease and related disorders.