Currently, neurodegenerative diseases are viewed as proteinopathies. In this context, a specific protein or peptide is involved in the pathogenesis of the disease by missfolding, polymerization, reduced degradation and final accumulation in the form of insoluble inclusions leading to neurodegeneration by various interacting mechanisms [1,2] . In Alzheimer's disease extracellular beta amyloid peptides and intracellular hyperphoshorylated tau proteins accumulate in the brain. In parkinsonian syndromes alpha synuclein (α-Syn) or 4R tau isoforms are found in various cytoplasmic inclusions.In about 50% of patients with frontotemporal lobar degeneration (FTLD) [3] and about 90% of patients with amyotrophic lateral sclerosis (ALS) [4] , the responsible protein is the transactive response DNA binding protein-43 (TDP-43), forming ubiquitinated inclusions. The two clinical conditions may coexist in the same patient or the same family with TDP-43 being the major culprit in the ALS-FTLD spectrum [5] .In an elegant study, Dong and Chen [6] extensively reviewed the pathogenetic mechanisms of ubiquitinated TDP-43 in ALS, including abnormal aggregation with pathologic accumulation (oligo-and finally polymerization), redistribution from the nucleus to the cytoplasm, reduced clearance by autophagy and/or the ubiquitine-proteasome system, neurotoxicity and/or loss of function, complex interactions with other proteins and RNA affecting their function and prion-like behavior and spreading. Such an understanding of TDP-43 and its role in the mechanisms of the resulting proteinopathy, may prove to be important in two aspects, diagnosis and treatment.