== Another key feature of prion-like mechanisms is the cell-to-cell spread of misfolded aggregates. on a prion-like mechanism. Keywords: ALS (Amyotrophic lateral sclerosis), SOD1, TDP-43, FUS, Plion-like phenomena, Misfolded protein aggregates == INTRODUCTION == The motor neuron diseases (MND) are a class of progressive neurologic diseases characterized by selective degeneration of the motor neurons that govern voluntary muscle movement [1]. Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, is the most common form of motor neuron disease. It is a fatal adult-onset (the average disease onset age is approximately Desoximetasone 50 years) neurodegenerative disease, and major characteristic symptoms of ALS include muscle weakness, spasticity, atrophy, paralysis and premature death [2]. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. However , approximately 10% of patients survive more than ten years [3]. The incidence rate of ALS is 2 out of 100, 000 individuals per year, and the average age of onset is approximately 50 years [2]. ALS is sporadic in 95% of patients and seems to occur randomly throughout the population (called Sporadic ALS (SALS)). The remaining 5% of ALS patients have at least one affected first degree relative (familial ALS (FALS)) [4]. There is no cure for ALS, Desoximetasone and riluzole, the only FDA-approved drug for ALS treatment, extends survival by only a few months [5]. Thus, the search for novel therapeutic approaches is warranted. The first identified ALS disease gene wasSOD1(copper zinc superoxide dismutase 1), which was found in 1993 [6]. Thanks to recent advances in sequencing and genotyping technology, many new genetic mutations have been identified in FALS and SALS patients. These mutations are found in theHNRNPA1, PFN1, TAF15, ATXN2, C9ORF72, UBQLN2, OPTN, VCP, FUSandTARDBPgenes [4, 7]. Interestingly, the most prominent histopathological hallmark of ALS is the accumulation of misfolded oligomers or protein inclusions containing TDP-43, FUS or SOD1 protein [2]. Moreover, most ALS patients have dense TDP-43 aggregates in affected neurons and glia in the CNS [8]. Despite protein collectiong being a prominent pathological hallmark of ALS, many questions still need to be addressed, especially regarding the pathological role and formation mechanism of these protein aggregates [4]. Recently, it was proposed that cell to cell transmission of misfolded protein aggregates (a prion-like mechanism) may directly contribute to the generation of novel protein aggregates and the propagation of neurodegeneration in ALS and other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease [9, 10, 11, 12, 13]. In this review, we highlight the recent findings implicating a prion-like mechanism as a key player in Rabbit Polyclonal to RPL19 neurodegeneration in ALS patients and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism. == PRION-LIKE PHENOMENA IN ALS == Transmissible spongiform encephalopathies (TSEs), also called prion diseases, are fatal neurodegenerative diseases of mammals. The infectious agent of TSEs is a misfolded protein, referred to as PRPsc[14]. PRPscaggregates can self-propagate and elongate by binding to monomers of PrPc(normal prion protein) [15]. There are a number of similarities between TSEs and ALS. First of all, ALS patients have an aggregate structure that contains a misfolded self-protein in their affected neurons. Furthermore, recent cultured cell line and animal model studies suggest that the misfolded forms of SOD1 and TDP-43 do self-propagate within neuronal cells and transmit to neighboring cells [9, 12, 16]. One of the most well-known clinical observations of ALS is focal onset of motor weakness in the spinal and bulbar regions and contagious spreading of Desoximetasone the disease [17]. Interestingly, intensive autopsy.