In Huntington’s, Dysfunctions of Neuronal Pathways Are Broad and Shared

In a recent review entitled “Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways,” published in the BMC Neuroscience journal, researchers discuss neuronal alterations caused by aberrant protein aggregations in neurodegenerative disorders such as Huntington’s, Alzheimer’s, Parkinson’s and Prion diseases, which eventually results in neuronal death. Understanding the interplay between all these neurodegenerative pathways may allow for the development of efficient therapies against these diseases.

The aggregation and deposition of misfolded proteins is the main cause of neuronal malfunction and degradation in neurodegenerative disorders. Independently of protein aggregates nature, these toxic molecular elements elicit degenerative neuronal responses which are shared among different neurological diseases. In their study, researchers review the effects of neurodegenerative protein aggregates in glycogen synthase kinase-3 beta (GSK-3beta) and mitogen-activated protein kinases (MAPK) activity, in cellular trafficking, cell cycle modulation, and oxidative stress.

GSK-3beta and MAPK are important signaling proteins that mediate several cellular processes, such as glycogen metabolism, gene transcription, and cellular trafficking. Misfolded protein aggregates — such as those formed by beta-amyloid and alpha-synuclein — affect those signaling activities resulting in broad cellular dysfunctions. Toxic protein elements also affect intracellular trafficking by interfering with microtubules stability, further contributing to cellular trauma. Moreover, these molecular aggregates also affect mitochondria functions and stability, affecting neurons oxidative species clearance ability, causing extensive cellular oxidative stress. Altogether, these events lead to a progressive neuronal degeneration and cell death.

The review shows that even though some aspects of the pathological events leading to cell death in neurodegenerative disorders can be disease specific, many others are common with substantial overlap. Neuronal death in these disorders is not elicited by a single cause event, but rather by a combination of several altered responses. Understanding the interplay between all these neurodegenerative pathways is of utmost importance and could open a window on promising therapeutic interventions.