Volume 7 Issue 11, November 2011

A recent study has identified mutations in the ubiquilin 2 gene in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS–dementia. The results suggest that ubiquilin 2 inclusions and impairment of the protein degradation pathway contribute to the pathogenesis of ALS and possibly other neurodegenerative disorders.

Glial cell line-derived neurotrophic factor (GDNF) has proved efficacious in treatment of neurodegeneration in toxin-induced models of Parkinson disease (PD), but clinical trials have been equivocal. Do the results of a recent study—suggesting that GDNF is ineffective in an α-synuclein-overexpression PD model—exclude GDNF as a therapy for PD?

Until the early 1990s, the prevailing view was that amyotrophic lateral sclerosis (ALS) was rarely familial, but subsequent genetic discoveries have overturned this idea. Andersen and Al-Chalabi document the rapidly changing genetic landscape in ALS, highlighting the lack of a clear distinction between heritable and apparently sporadic ALS, and providing recommendations for genetic counseling.

An improved understanding of the cellular events that lead to motor neuron injury in amyotrophic lateral sclerosis (ALS) could highlight promising new therapeutic strategies. Pamela Shaw and colleagues provide a comprehensive overview of the numerous molecular mechanisms that are involved in ALS, including oxidative stress, mitochondrial dysfunction and excitotoxicity. They discuss features specific to motor neurons that might render this cell type vulnerable to damage, and highlight important links between cellular events and clinical features of the disease.

Research into amyotrophic lateral sclerosis (ALS) has improved our understanding of the molecular mechanisms underlying disease pathogenesis, but diagnosis of patients with ALS has remained difficult. Bowseret al. highlight recent discoveries of biomarkers for ALS—from proteins in biofluids to neurophysiological and neuroimaging findings—and discuss the benefits and limitations of these biomarkers as diagnostic and prognostic indicators of disease.

Amyotrophic lateral sclerosis is a devastating neurodegenerative motor neuron disease that results in progressive loss of bulbar and limb function. In this Review, Hardiman et al. provide an overview of the clinical aspects of the disease, discussing epidemiology, clinical presentation, diagnosis and management, with an emphasis on recent key advances.

Clinical trials for amyotrophic lateral sclerosis have failed to yield a single new drug over the past 17 years. In their Opinion article, Gordon and Meininger provide insights into possible reasons for the lack of success, such as the heterogeneity of the disease, limitations of preclinical models, and the choice of clinical end points. They also present possible strategies to address the ongoing challenges, including appropriate dose selection and development of suitable biomarkers.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease that presents substantial diagnostic and therapeutic challenges. In this focus issue, experts highlight recent progress in understanding the genetic and molecular underpinnings of ALS, including the discovery of biomarkers for rapid diagnosis of the condition and monitoring of disease progression. Current and future treatment and management approaches are also addressed, along with prospects for improving the design of clinical trials in ALS.