. A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies. JAMA Neurol. 2013 Apr 15;:1-9. PubMed.

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  1. This study confirms links between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutations, expanding on several other studies that have shown links between GBA and Parkinson's disease (PD)/DLB. The strengths of this study are its multicentric nature and the large number of samples that greatly increase confidence. Besides this, consideration of the data leads to two other thoughts.

    A longstanding debate in the field is whether PD and DLB are distinct diseases, or fall within the same spectrum. Clinically, dementia is seen in about half of PD patients, and occasional Lewy bodies (LBs) in the neocortex are not uncommon in “PD”—as every neuropathologist knows. So my humble personal bias has been that, generally speaking, PD and DLB are diseases within the same spectrum, though there are exceptions and caveats to this rule. As is typical, evidence that could really change one’s mind comes from the quantitative realm of genetics. Specifically, studies such as this, showing GBA mutations in both PD and DLB, and also other studies showing that multiplications and mutations of α-synuclein can lead to either PD or DLB (1-3), support the view that there are common mechanistic threads between these two diseases and that they both fall within the same spectrum. What can these common mechanistic events be?

    An important clue comes from the knowledge that genetic multiplications of α-synuclein—even in rare sporadic cases (4)—lead to disease. Combined with the view that GBA mutations can decrease degradation of α-synuclein—effectively increasing its concentration within the cell—the collective evidence suggests common downstream mechanistic events that are secondary to elevated α-synuclein (protein) levels. As α-synuclein is a synaptic protein, we and others have proposed that such events occur at synapses first (5-8). Specifically, our data suggest that increased α-synuclein levels lead to decreases in neurotransmitter release, and this may relate to the normal function of this protein (5,6). A recent study looking at neurotransmission and dopaminergic neuronal pathology in an in-vivo α-synuclein overexpressing model shows early attenuations in exocytosis, supporting the “synaptocentric” view (9). Resolving various primary and secondary pathophysiologic links in these pathways is the next big challenge.

    References:

    . Clinicopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology. 2008 Jan 15;70(3):238-41. PubMed.

    . Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol. 2004 Feb;55(2):174-9. PubMed.

    . Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson's disease. Variability in familial Parkinson's disease. Acta Neuropathol. 2008 Jul;116(1):25-35. PubMed.

    . Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann Neurol. 2008 Jun;63(6):743-50. PubMed.

    . A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci. 2010 Jun 16;30(24):8083-95. PubMed.

    . α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis. J Neurosci. 2012 Jul 25;32(30):10129-35. PubMed.

    . Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010 Jan 14;65(1):66-79. PubMed.

    . Alpha-synuclein overexpression in mice alters synaptic communication in the corticostriatal pathway. J Neurosci Res. 2010 Jun;88(8):1764-76. PubMed.

    . Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3213-9. PubMed.

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