Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways

Abstract

Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed.

α-Synuclein binds to the ER–mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production

“…However, for TDP-43 and FUS, this breaking involves activation of GSK-3β; GSK-3β is a regulator of the VAPB–PTPIP51 interaction and so controls ER–mitochondria associations and Ca 2+ exchange [78, 79]. GSK-3β has been linked to α-synuclein and Parkinson’s disease [27, 54, 57] but we found no evidence that either wild-type or mutant α-synuclein expression caused activation of GSK-3β. Rather, we found that α-synuclein bound directly to VAPB.…”

A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer’s Disease and Mild Cognitive Impairment

“…Both the mechanisms and implications of this finding remain incompletely defined, but suggestions that neurodegeneration-related proteins may interact, and that α-syn, Aβ and tau may mutually accelerate their accumulation and aggregation, are abundant[19, 35]. Both AD and PD feature impaired cellular mechanisms for clearing abnormal proteins, contributing to the burden of pathological proteins and their deleterious effects on neurons[36–38]. There is also evidence that intra-axonal α-syn and intraneuronal tau aggregates are associated with axonopathy and cellular dysfunction[39].…”

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

“…Furthermore, J20 mice expressing high level of hAPP showed the presence of DSB marker γH2AX in brain, suggesting a possible link between Aβ accumulation and increased DSBs formation [21]. Similarly, the presence of toxic α-Syn aggregates inhibits the mitogen activated protein kinase (MAPK) pathway, alters axonal trafficking and induces oxidative stress [189], leading to the accumulation of 8-oxoG in both the mtDNA and nuDNA of DAergic neurons in PD. While Aβ and α-Syn toxicity could cause genome damage via multiple mechanisms, some studies have indicated that misfolded amyloid proteins could interfere with the repair process due to their DNA binding activity.…”