The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia

Abstract

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are usually associated with loss of dopaminergic neurons. Loss of substantia nigra neurons and presence of Lewy body inclusions in some of the remaining neurons are the hallmark pathology seen in the final stages of the disease. Attempts to correlate Lewy body pathology to either cell death or severity of clinical symptoms, however, have not been successful. While the pathophysiology of the neurodegenerative process can hardly be explained by Lewy bodies, the clinical symptoms do indicate a degenerative process located at the presynapse resulting in a neurotransmitter deficiency. Recently it was shown that 90% or even more of α-synuclein aggregates in DLB cases were located at the presynapses in the form of very small deposits. In parallel, dendritic spines are retracted, whereas the presynapses are relatively preserved, suggesting a neurotransmitter deprivation. The same α-synuclein pathology can be demonstrated for PD. These findings give rise to the notion that not cell death but rather α-synuclein aggregate-related synaptic dysfunction causes the neurodegeneration. This opens new perspectives for understanding PD and DLB. If presynaptic α-synuclein aggregation, not neuronal loss, is the key issue of the neurodegenerative process, then PD and DLB may eventually be treatable in the future. The disease may progress via trans-synaptical spread, suggesting that stem cell transplants are of limited use. Future therapies may focus on the regeneration of synapses.

Impaired synaptic function is linked to cognition in Parkinson's disease

“…Although we find strong links to A β , a reverse causality cannot be excluded, in that synaptic dysfunction could be due to presynaptic α ‐synuclein aggregates slightly reducing A β in proportion to the degree of α ‐synuclein‐dependent neurodegeneration 5, 45. Alternatively, defective presynaptic proteolysis and lysosomal degradation could affect both A β and α ‐synuclein metabolism 7, 8, 46.…”

“…In AD, increased CSF neurogranin concentrations probably reflects synaptic degeneration with loss of integrity of postsynaptic spines, that results in increased CSF levels, and this is hypothesized specifically for Alzheimer's disease 37, 38. In PD, cortical presynaptic pathology has been demonstrated in the form of accumulation of α ‐synuclein oligomers, accompanied by loss of dendritic spines but other postsynaptic injury was not described 5. This is consistent with our present findings of a reduced CSF neurogranin in the present PD population as compared to healthy controls.…”

“…Many of the proteins relevant in PD pathophysiology are involved in synaptic physiology (reviewed in3). α ‐synuclein is considered the core pathological substrate of PD, and in addition to accumulation in Lewy bodies, a major deposition site of CNS oligomeric α ‐synuclein is the presynapse, accompanied by transsynaptic dendritic spine loss 4, 5. The presynaptic terminal is the main site of function for both amyloid precursor protein (APP) and α ‐synuclein.…”

Striatal Blood–Brain Barrier Permeability in Parkinson'S Disease

“…1 This is conceivable within the paradigm of retrograde (axon terminal to soma) Lewy pathology spread. 2,3 Almost all regions affected in Braak stage 1 have axon terminals outside the blood-brain barrier (BBB). That same BBB, however, protects the higher-order regions, whose axon terminals reside within the central nervous system, from blood-borne substances.…”

Neural stem cells: mechanisms and modeling

“…PD is the second most common neurodegenerative disease and is characterized by motor symptoms including bradykinesia, tremor, rigidity and postural instability, as well as some non-motor-related symptoms such as sensory dysfunction and sleep disorders. The pathogenesis of PD is caused by the accumulation of misfolded alpha-synuclein into the intracellular Lewy bodies (Aarsland et al, 2009;Schulz-Schaeffer, 2010;Vekrellis et al, 2011) and insufficient dopamine expression in neurons in the substantia nigra of the midbrain (Goedert, 2001;Braak et al, 2007). Fibroblasts from PD patients have been successfully reprogrammed and differentiated into dopamine neurons (Park et al, 2008;Soldner et al, 2009).…”