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 . 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 50 years ) neurodegenerative disease , and major characteristic symptoms of als include muscle weakness , spasticity , atrophy , paralysis and premature death . 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 . the incidence rate of als is 2 out of 100,000 individuals per year , and the average age of onset is approximately 50 years . 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 ) ) . there is no cure for als , and riluzole , the only fda - approved drug for als treatment , extends survival by only a few months . the first identified als disease gene was sod1 ( copper zinc superoxide dismutase 1 ) , which was found in 1993 . 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 the hnrnpa1 , pfn1 , taf15 , atxn2 , c9orf72 , ubqln2 , optn , vcp , fus and tardbp genes . interestingly , the most prominent histopathological hallmark of als is the accumulation of misfolded oligomers or protein inclusions containing tdp-43 , fus or sod1 protein . moreover , most als patients have dense tdp-43 aggregates in affected neurons and glia in the cns . despite protein aggregation 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 . 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 . in this review , we highlight the recent findings implicating a prion - like mechanism as a key player in neurodegeneration in als patients and discuss the possible therapeutic strategies for als based on a prion - like mechanism . transmissible spongiform encephalopathies ( tses ) , also called prion diseases , are fatal neurodegenerative diseases of mammals . prp aggregates can self - propagate and elongate by binding to monomers of prp ( normal prion protein ) . 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 . 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 the disease . interestingly , intensive autopsy studies of postmortem als patients show that the loss of lower motor neurons is most apparent at the region of onset and decreases in a graded manner with further distance from the anatomic location of disease onset . these clinical data indicate that neurodegeneration in als is an orderly propagating process , which seems to share the signature of seeded self - propagation with pathogenic prion proteins . despite a number of parallels between prion disease and als , prion diseases can be transmitted through an animal population via oral uptake , blood transfusion or other sources of direct contact . tdp-43 and sod1 misfolded protein aggregates found in als patients can induce the misfolding of their normally structured counterparts ; however , at least under natural circumstances , als is not an infectious disease . therefore , we should differentiate the terms " prion " and " prion - like " . the term " prion - like mechanism " will be used to identify the molecular mechanisms that share common features with the self - propagation and spreading characteristics of prion proteins . a summary of the evidence implicating the prion - like mechanism within als is shown in table 1 . native sod1 forms a very stable homodimer , but almost all als - linked sod1 mutations are susceptible to partial unfolding at physiological ph and temperature . furthermore , mutant sod1-containing insoluble inclusions are highly accumulated within affected motor neurons of sod1-related fals patients . transgenic mice expressing human sod1 with a pathogenic mutation very accurately recapitulate common characteristics of als such as the selective progressive loss of motor neurons and a progressive loss of motor activity . sod1-positive inclusions found in human patients and fals mouse - models show identified granule - coated fibrillar morphologies . fibrillar protein aggregates that are rich in -sheet structures act as a structural template to convert normal proteins into a misfolded structure and then elongate the protein fibril . it is not clear if sod1-containing inclusions of fals patients are -sheet rich fibrils , but fibrillar aggregates of the sod1 mouse model contain amyloid - like aggregates with a -pleated sheet . moreover , spinal cord homogenates of transgenic mice expressing the als - linked g93a - mutant human sod1 protein triggered amyloid - like fibril formation of purified wild type and mutant sod1 protein . other studies also show that wild type and mutant misfolded sod1 proteins can induce misfolding of cell - endogenous normal structured wild type sod1 in a physiological intracellular environment . removed misfolded mutant sod1 proteins using a mutant form specific antibody ( gx - ct ) in a hek cell line expressing the sod1 g127x mutant , but this removal of misfolded seeds did not prevent aggregation of endogenous sod1 . this result indicates that the newly generated misfolded sod1 also act as a template for the self - propagation of misfolded sod1 aggregates . as mentioned above , many studies suggest that misfolded sod1-containing fibrils can act as a structural template for a " prion - like replication " from native - structured protein to insoluble misfolded conformers . misfolded fibrils can be elongated by this conversion process of the normal protein . breakage of misfolded fibrils is important for this self - propagation process because sheared pieces of misfolded fibrils can be propagated through the template - assisted misfolding of native protein . this self - propagation process is analogous to the replication of infectious prion aggregates ( fig . another key feature of prion - like mechanisms is the cell - to - cell spread of misfolded aggregates . another possible process is cell death induced leakage of misfolded seeds . the death of affected cells releases aggregated protein into the extracellular environment , and then neighboring cells can take up these aggregates by phagocytosis ( fig . therefore , there is a high possibility that seed spreading by cell death is implicated in cell - to - cell transmission of misfolded aggregates . a recent study reported that purified als - linked sod1 mutant aggregates ( sod1 ) effectively penetrate into cells and convert the endogenous wild type sod1 to misfolded aggregates in the neuro-2a cell line . these aggregates are continuously released by cells and taken up into neighboring cells via macropinocytosis . these findings indicate that als - linked sod1 aggregates have prion - like properties such as self - perpetuation and the transmission of the misfolded pathological proteins to adjacent cells . misfolded aggregate spreading mediated by secreted mutant sod1 may not be limited to neuron to neuron propagation . it is very well accepted that secreted toxic factors produced by glial cells expressing als - causing mutant sod1 induce the loss of motor neurons in the fals sod1 mouse model . using astrocytes derived from neural progenitor cells from the postmortem tissues of als patients , haidet - phillps et al . demonstrated that astrocytes generated from tissues from als patients are toxic to motor neurons derived from non - als postmortem tissues . importantly , knock - down of sod1 in als tissue - derived astrocytes was found to mitigate the motor neuron toxicity of these astrocytes . these findings indicate that the generation of a glial cell released factor that is toxic to motor neurons is dependent on the glial sod1 protein . furthermore , overexpression of als - linked mutant sod1 in astrocytes induced an increase in exosome release , and those astrocyte - produced exosomes contained mutant sod1 proteins . not surprisingly , mutant sod1 was transmitted to the cytoplasm of spinal neurons through astrocyte - released exosomes . however , additional experimental studies are required to prove that secretory vesicles released from glial cells act as a messenger for misfolded seeding protein . tar dna binding protein ( tdp-43 , 43 kda ) is a highly conserved rna / dna binding protein involved in various rna processing pathways including stress granule formation and rna splicing . tdp-43 is a major component of pathological inclusions found in spinal cord motor neurons , hippocampal and frontal cortex neurons and glial cells in most sals and sod1-negative fals cases . under normal conditions , most tdp-43 protein is localized in the nucleus , however , in als patients , neurons with cytoplasmic tdp-43 aggregates often showed a corresponding reduction of the nuclear tdp-43 level . genetic studies have identified tardbp ( which encodes tdp-43 ) mutations in ~4% of fals cases and a small percentage of sals cases . following the identification of tardbp mutations in als patients , other fals mutations were identified in fus which also encodes the rna binding protein fus . 3 ) , and both purified tdp-43 and fus can easily aggregate in vitro . furthermore , both tdp-43 and fus contain a prion - like glutamine / asparagine rich domain that shares similarities with yeast prion protein , and this domain is essential for amyloid - like fiber polymerization in cell - free models of rna granule formation . like sod1 proteins , the als - causing tdp-43 mutation enhances neurotoxicity and abnormal aggregate formation , and the c - terminal domain is essential for this aggregation process . moreover , almost all als linked tdp-43 mutations are found in the c - terminal region , and c - terminal truncated fragments of tdp-43 show significantly enhanced aggregation properties in vitro and in cells . taken together , these data suggest that tdp-43 positive neuronal cytoplasmic inclusions are driven by the prion - like c - terminal domain of tdp-43 and that pathologic aggregation process is accelerated by als - linked tdp-43 mutations . a recent study reported that the recombinant tdp-43 protein forms sarkosyl - insoluble fibrillar aggregates in vitro , and transduction of these tdp-43 fibrils into cultured hek293 t cells overexpressing tdp-43 induces fibrillation of the endogenous tdp-43 . nonaka et al . also demonstrated that the introduction of detergent insoluble tdp-43 aggregates from als or ftld - tdp patients into sh - sy5y cells expressing tdp-43 induces aggregation of phosphorylated and ubiquitinated tdp-43 in a prion - like , self - templating manner . in addition , phosphorylated tdp-43 aggregates are transmitted between cultured cells , and intracellular tdp-43 aggregates are associated with exosomes . based upon these results , the prion - like properties of tdp-43 may contribute to the pathological mechanism of als . it remains to be determined whether fus also shows prion - like propagation , but recent studies have reported that an als - causing mutant of fus forms amyloid - like fibrillar aggregates , and these fibrils act as seeds to trigger the aggregation of wild - type fus in vitro . accumulating evidence suggests that the prion - like mechanism of tdp-43 and fus plays an important role in als pathogenesis ; however , further studies are needed to elucidate their exact mechanism of action and pathological effect . the focality of clinical onset and regional spreading of neurodegeneration are typical features of als . one of the possible models for the progression of als would be the spreading of toxic misfolded seeds from a focal site . if a prion - like mechanism represents key components of disease progression and persistence , antibody - based drug development could be possible . antibodies could promote break - down of misfolded - aggregates and block their ability to act as a nucleation seed or penetrate into neighboring cells . interestingly , intracerebroventricular infusion of monoclonal antibodies specific to misfolded sod1 extends the lifespan of mice with als ( g93a - sod1 mouse model ) . another promising therapeutic strategy for als involves elucidating the shared pathological mechanism between als and prion diseases . recent studies indicate that elevation of the eif2-phosphorylation level is a common feature of prion diseases and als models . strikingly , downregulation of eif2-phosphorylation by perk inhibitor treatment mitigates the toxicity of prion proteins and tdp-43 [ 39 , 41 ] . consequently , dissecting the molecular mechanism of a prion - like process may yield valuable insights into developing therapeutic strategies for als . therefore , lessons and tools from the prion field may become useful for future research on als .
als is a fatal adult - onset motor neuron disease . 
 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 . 
 the major pathological hallmark of als is abnormal accumulation of protein inclusions containing tdp-43 , fus or sod1 protein . 
 moreover , the focality of clinical onset and regional spreading of neurodegeneration are typical features of als . 
 these clinical data indicate that neurodegeneration in als is an orderly propagating process , which seems to share the signature of a seeded self - propagation with pathogenic prion proteins . in vitro and cell line experimental evidence 
 suggests that sod1 , tdp-43 and fus form insoluble fibrillar aggregates . 
 notably , these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts . 
 collectively , a self - propagation mechanism similar to prion replication and spreading may underlie the pathology of als . in this review , we will briefly summarize recent evidence to support the prion - like properties of major als - associated proteins and discuss the possible therapeutic strategies for als based on a prion - like mechanism .