Novel molecular alterations in amyotrophic lateral sclerosis and frontotemporal lobar degeneration spectrum

Resumen

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are clinically distinct neurodegenerative diseases that are connected by genetic and pathological overlap. ALS patients present with muscle weakness and spasticity associated with degeneration of motor neurons in the motor cortex, brainstem, and spinal cord that ultimately leads to death. In contrast, patients with FTLD display cognitive dysfunction associated with degeneration of neurons in the frontal and temporal lobes of the brain. Despite being clinically distinct, 15% of individuals presenting FTLD also have ALS, whereas 30% of individuals with ALS will develop FTLD. This implies that these two neurodegenerative diseases are part of a shared clinical spectrum. In recent years, several mechanisms have been proposed as contributory factors in the pathogenesis of neuron damage in ALS and FTLD, including excitoxicity, mitochondrial and energy metabolism failure, oxidative stress damage, altered glial cells, inflammation, cytoskeletal abnormalities, alterations in RNA metabolism, and altered TDP-43 metabolism, among others. However, it is poor known about the etiology of these disorders and their possible treatment. The objective of the investigations presented in this doctoral thesis is focused in the identification of new molecular alterations underlying motor and cognitive changes in post-mortem human spinal cord and brain samples of ALS patients and brain samples of FTLD-TDP patients compared with controls, combining microarray, mRNA, protein and enzyme assays studies. The obtained results have identified molecular alterations in ALS and FTLD of different biological functions and cellular pathways including changes in mitochondrial energy metabolism, neuroinflammation, neuronal structure, neurotransmission, axonal transport mechanisms and oligodendrocyte function; allowing in turn, the screening and identification of new candidate molecules as biomarkers for these disorders.