A Major Genetic Factor at Chromosome 9p Implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative diseases for which effective therapies aiming at delaying, halting or preventing the disease are lacking. ALS is the most common motor neuron disorder (Rowland & Shneider, 2001) and FTLD has a prevalence close to that of Alzheimer disease in the population below age 65 years (Rosso et al., 2003). They are considered as both extremes of a spectrum of clinically and pathologically overlapping disorders (Lillo & Hodges, 2009). In addition, there is emerging evidence that FTLD and ALS also share common genetic aetiologies, suggesting that overlapping disease mechanisms are involved in both diseases. Clinically, ALS patients show reduced control of voluntary muscle movement expressed in increased muscle weakness, disturbances of speech, swallowing or breathing, as a result of progressive upper and lower motor neuron degeneration in motor cortex, brainstem and spinal cord, and up to 50% of ALS patients shows mild disturbances in executive functions while a minority also develop overt FTLD (Lomen-Hoerth et al., 2003; Ringholz et al., 2005). FTLD symptoms include behavioural, personality and language disturbances, and also cognitive dysfunctions, due to affected frontal and temporal cortical neurons in the brain. FTLD patients may additionally present with typical clinical signs of ALS in a later stage of the disease (Neary et al., 1998). Pathologically, although in different neuronal cells, TAR DNA-binding protein-43 (TDP-43) is a major constituent of neuronal deposits in both ALS and TDP-43 positive FTLD (FTLD-TDP), the most common pathological FTLD subtype (Arai et al., 2006; Neumann et al., 2006). Five to 10% of ALS patients and up to 50% of FTLD patients has a positive familial history of disease with a Mendelian mode of inheritance indicating a significant contribution of genetic factors in disease aetiology. Although the exact biochemical pathways involved in ALS or FTLD are still unknown, several molecular components were identified in the last twenty years through molecular genetic studies in familial and sporadic patients, which are most likely part of a complex network of cellular mechanisms. Since these genes explain only a minority of patients, further unraveling the