Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis. An Update on a Lasting Relationship

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu–Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial “metabolic threshold”, which may appear pivotal in ALS pathogenesis

Effects of head trauma and sport participation in young-onset Parkinson’s disease

Head trauma (HT) is emerging as an event anticipating onset of neurodegenerative disorders. However, the potential contribution of HT in young-onset cases (YOPD, age at onset < 50) of Parkinson’s disease (PD) has not been examined yet. Here, we systematically assessed HT history in PD patients to estimate the risk associated, especially in terms of age of onset, and define the correlations with the clinical-biochemical profile. The Brain Injury Screening Questionnaire (BISQ) was administered to 94 PD patients (31 with YOPD, known monogenic forms excluded) and 70 controls. HT history was correlated with motor and non-motor scores in all patients, and to CSF biomarkers of neurodegeneration (α-synuclein, amyloid-β42, total and phosporiled-181 tau, lactate, CSF/serum albumin) into a subgroup. HT increased the risk for both PD and YOPD. In PD patients, but not in those with YOPD, the number of HTs directly correlated with CSF total-tau levels. No other correlations resulted between HT and clinical parameters. Sport-related HT was a specific risk factor for YOPD; conversely, the prolonged sporting life represented a protective factor. HTs can favor PD onset, even as YOPD. Sport-related HT resulted a risk factor for YOPD, although the longer sporting practice delayed PD onset, protecting from YOPD. Tauopathy may underlie the overall association between HT and PD. Additional mechanisms could be instead implicated in HT contribution to YOPD onset