Impaired 26S Proteasome Assembly Precedes Neuronal Loss in Mutant UBQLN2 Rats.

Proteasomal dysfunction is known to be associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). Our previous reports have shown that a mutant form of ubiquilin-2 (UBQLN2) linked to ALS/FTD leads to neurodegeneration accompanied by accumulations of the proteasome subunit Rpt1 in transgenic rats, but the precise pathogenic mechanisms of how this mutation impairs the proteasome remains to be elucidated. Here, we reveal that this UBQLN2 mutation in rats disrupted the proteasome integrity prior to neurodegeneration, that it dissociated the 26S proteasome in vitro, and that its depletion did not affect 26S proteasome assembly. During both disease progression and in an age-dependent manner, we found that proteasome subunits were translocated to the nucleus, including both of the 20S core particles (PSMA1 and PSMB7) and the 19S regulatory particles (Rpt1 and Rpn1), suggesting that defective proteasome function may result from the proteasome-subunit mislocalization. Taken together, the present data demonstrate that impaired proteasome assembly is an early event in the pathogenesis of UBQLN2-associated neurodegeneration in mutant UBQLN2 rats.

C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two clinically distinct classes of neurodegenerative disorders. Yet, they share a range of genetic, cellular, and molecular features. Hexanucleotide repeat expansions (HREs) in the C9orf72 gene and the accumulation of toxic protein aggregates in the nervous systems of the affected individuals are among such common features. Though the mechanisms by which HREs cause toxicity is not clear, the toxic gain of function due to transcribed HRE RNA or dipeptide repeat proteins (DPRs) produced by repeat-associated non-AUG translation together with a reduction in C9orf72 expression are proposed as the contributing factors for disease pathogenesis in ALS and FTD. In addition, several recent studies point toward alterations in protein homeostasis as one of the root causes of the disease pathogenesis. In this review, we discuss the effects of the C9orf72 HRE in the autophagy-lysosome pathway based on various recent findings. We suggest that dysfunction of the autophagy-lysosome pathway synergizes with toxicity from C9orf72 repeat RNA and DPRs to drive disease pathogenesis.Abbreviation: ALP: autophagy-lysosome pathway; ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: autophagy-related; ASO: antisense oligonucleotide; C9orf72: C9orf72-SMCR8 complex subunit; DENN: differentially expressed in normal and neoplastic cells; DPR: dipeptide repeat protein; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; ER: endoplasmic reticulum; FTD: frontotemporal dementia; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; HRE: hexanucleotide repeat expansion; iPSC: induced pluripotent stem cell; ISR: integrated stress response; M6PR: mannose-6-phosphate receptor, cation dependent; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MN: motor neuron; MTORC1: mechanistic target of rapamycin kinase complex 1; ND: neurodegenerative disorder; RAN: repeat-associated non-ATG; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SLC66A1/PQLC2: solute carrier family 66 member 1; SMCR8: SMCR8-C9orf72 complex subunit; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; WDR41: WD repeat domain 41.

Pathophysiological implications of RNP granules in frontotemporal dementia and ALS.

Neurodegenerative diseases are a group of chronic, progressive, age-related disorders that are becoming increasingly prevalent in the ageing population. Despite the variety of clinical features observed, neurodegenerative diseases are characterised by protein aggregation and deposition at the molecular level. The nature of such intracellular protein aggregates is dependent on disease type and specific to disease subtype. Frontotemporal dementia and amyotrophic lateral sclerosis (ALS) are two overlapping neurodegenerative diseases, exhibiting pathological aggregates commonly composed of the proteins: Fused in Sarcoma (FUS) or Transactive Response DNA Binding Protein of 43 KDa (TDP-43). The presence of these protein aggregates in late disease stages is suggestive of a converging underlying mechanism of pathology across diseases involving disrupted proteostasis. Despite this, at present there are no effective therapeutics for the diseases, with current treatment strategies generally tending to be only for symptom management. An area of research that has gained increased interest in recent years is the formation and maintenance of ribonucleoprotein (RNP) granules. These are membraneless organelles that consist of RNA and protein elements, which can be either constitutively expressed (such as nuclear paraspeckles) or upregulated under conditions of cellular stress as an adaptive response (such as cytoplasmic stress granules). RNA-binding proteins are a key component of RNP granules, and crucially some of which, for example FUS and TDP-43, are also neurodegenerative disease-associated proteins. Therefore, a better understanding of RNA-binding proteins in RNP granule formation and the regulation and maintenance of RNP granule biophysical properties and dynamics may provide insights into mechanisms contributing to disrupted proteostasis in neurodegenerative pathology; and thus open up new avenues for therapeutic discovery and development. This review will focus on stress granule and paraspeckle RNP granules, and discuss their possible contribution to pathology in cases of frontotemporal dementia and ALS.

Transcranial magnetic stimulation and amyloid markers in mild cognitive impairment: impact on diagnostic confidence and diagnostic accuracy.

BACKGROUND: The development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown. OBJECTIVE: To evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians' expertise. METHODS: One hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step. RESULTS: The addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p = 0.003), MCI-FTD (p = 0.044), and MCI-DLB (p = 0.033) compared to clinical work-up alone, but not for MCI-other (p > 0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p > 0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers. CONCLUSIONS: TMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis.

Emotion recognition in objects in patients with neurological disease.

OBJECTIVE: Considerable research indicates that individuals with dementia have deficits in the ability to recognize emotion in other people. The present study examined ability to detect emotional qualities of objects. METHOD: Fifty-two patients with frontotemporal dementia (FTD), 20 patients with Alzheimer's disease (AD), 18 patients awaiting surgery for intractable epilepsy, and 159 healthy controls completed a newly developed test of ability to recognize emotional qualities of art (music and paintings), and pleasantness in simple sensory stimuli (tactile, olfactory, auditory), and to make aesthetic judgments (geometric shapes, room décor). A subset of participants also completed a test of ability to recognize emotions in other people. RESULTS: Patients with FTD showed a marked deficit in ability to recognize the emotions conveyed in art, compared with both healthy individuals and patients with AD (relative to controls, deficits in patients with AD only approached significance). This deficit remained robust after controlling for FTD patients' ability to recognize pleasantness in simple sensory stimuli, make aesthetic judgments, identify odors, and identify emotions in other people. Neither FTD nor AD patients showed deficits in recognizing pleasant sensory stimuli or making aesthetic judgments. Exploratory analysis of patients with epilepsy revealed no deficits in any of these domains. CONCLUSION: Patients with FTD (but not AD) showed a significant, specific deficit in ability to interpret emotional messages in art, echoing FTD-related deficits in recognizing emotions in other people. This finding adds to our understanding of the impact these diseases have on the lives of patients and their caregivers. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Heterogeneity in the psychiatric presentation of behavioural variant frontotemporal dementia (bvFTD).

OBJECTIVE: This article describes how the onset of bvFTD can be heralded by psychiatric symptoms. METHOD: Case reports are described with reference to the relevant literature review. RESULTS: Three patients were admitted with psychiatric symptoms, including depression, mania, psychosis and catatonia. Two had been previously diagnosed with a psychiatric disorder. All three were diagnosed with probable bvFTD. CONCLUSION: bvFTD is an important differential diagnosis to consider when patients present with atypical psychiatric symptoms.

Screening for cognitive and behavioral change in amyotrophic lateral sclerosis/motor neuron disease: a systematic review of validated screening methods.

OBJECTIVES: Cognitive and behavioral change in Amyotrophic Lateral Sclerosis (ALS) is well-accepted. Several screening tools have been developed to detect such changes. Further guidance on their use may come from a consideration of the rigor with which they were validated. This systematic review set out to critically appraise and present published data pertaining to the validation of six screening tools used to diagnose cognitive and/or behavioral change in patients with ALS. METHODS: The screening tools considered in this search included: The Edinburgh Cognitive and Behavioural ALS Screen (ECAS), The ALS Cognitive Behavioural Screen (ALS-CBS), The Motor Neuron Disease Behavioural Scale (MiND-B), The Frontal Behavioural Inventory ALS Version, The ALS Frontotemporal Dementia Questionnaire (ALS-FTD-Q), and The Beaumont Behavioural Inventory (BBI). MEDLINE, EMBASE, and PsycINFO were searched until 4th week of June 2017. RESULTS: Fourteen eligible studies were included in the review. Papers either reported data concerning convergent validity or clinical validity. Validation data concerning the ECAS showed this screening tool to have strong clinical validity, although further work needs to consider how its use will affect diagnosis rates according to current diagnostic guidelines. When screening for behavioral change only, more limited information is available; the BBI may offer greater potential than the ALS-FTD-Q for detecting mild impairment as it assesses a wider range of behavioral changes. CONCLUSIONS: Scores of sensitivity, specificity, positive predictive values, and negative predictive values should be given considerable importance when considering which screening tools to incorporate into current clinical practice.

FUS-induced neurotoxicity in Drosophila is prevented by downregulating nucleocytoplasmic transport proteins.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases characterized by the progressive loss of specific groups of neurons. Due to clinical, genetic and pathological overlap, both diseases are considered as the extremes of one disease spectrum and in a number of ALS and FTD patients, fused in sarcoma (FUS) aggregates are present. Even in families with a monogenetic disease cause, a striking variability is observed in disease presentation. This suggests the presence of important modifying genes. The identification of disease-modifying genes will contribute to defining clear therapeutic targets and to understanding the pathways involved in motor neuron death. In this study, we established a novel in vivo screening platform in which new modifying genes of FUS toxicity can be identified. Expression of human FUS induced the selective apoptosis of crustacean cardioactive peptide (CCAP) neurons from the ventral nerve cord of fruit flies. No defects in the development of these neurons were observed nor were the regulatory CCAP neurons from the brain affected. We used the number of CCAP neurons from the ventral nerve cord as an in vivo read-out for FUS toxicity in neurons. Via a targeted screen, we discovered a potent modifying role of proteins involved in nucleocytoplasmic transport. Downregulation of Nucleoporin 154 and Exportin1 (XPO1) prevented FUS-induced neurotoxicity. Moreover, we show that XPO1 interacted with FUS. Silencing XPO1 significantly reduced the propensity of FUS to form inclusions upon stress. Taken together, our findings point to an important role of nucleocytoplasmic transport proteins in FUS-induced ALS/FTD.

Progranulin as a therapeutic target for dementia.

INTRODUCTION: Progranulin (PGRN) is an acrosomal glycoprotein that is synthesized during spermatogenesis. It is overexpressed in tumors and has anti-inflammatory properties. The protein may be cleaved into granulins which display pro-inflammatory properties. In 2006, mutations in progranulin gene (GRN) that cause haploinsufficiency were found in familial cases of frontotemporal dementia (FTD). Patients with null mutations in GRN display very low-plasma PGRN levels; this analysis is useful for identifying mutation carriers, independent of the clinical presentation, and in those before the appearance of symptoms. Areas covered: Here, we review the current knowledge of PGRN physiological functions and GRN mutations associated with FTD; we also summarize state of the art clinical trials and those compounds able to replace PGRN loss in preclinical models. Expert opinion: PGRN represents a promising therapeutic target for FTD. Cohorts suitable for treatment, ideally at the preclinical stage, where pathogenic mechanisms ongoing in the brain are targeted, are available. However, PGRN may have side effects, such as the risk of tumorigenesis, and the risk/benefit ratio of any intervention cannot be predicted. Furthermore, at present, the situation is complicated by the absence of adequate outcome measures.

Amyotrophic lateral sclerosis modifies progenitor neural proliferation in adult classic neurogenic brain niches.

BACKGROUND: Adult neurogenesis persists through life at least in classic neurogenic niches. Neurogenesis has been previously described as reduced in neurodegenerative diseases. There is not much knowledge about is adult neurogenesis is or not modified in amyotrophy lateral sclerosis (ALS). All previous publications has studied the ALS SOD1 (superoxide dismutase) transgenic mouse model. The purpose of this study is to examine the process of adult neurogenesis in classic niches (subventricular zone [SVZ] and subgranular zone [SGZ] of the dentate gyrus) in patients with amyotrophic lateral sclerosis (ALS), both with (ALS-FTD) and without associated frontotemporal dementia (FTD). METHODS: We studied 9 autopsies of patients with ALS (including 2 with ALS-FTD) and 4 controls. ALS was confirmed histologically. Studies of the SVZ and SGZ were conducted using markers of proliferation (Ki-67, PCNA), of pluripotent neural progenitor cells (GFAPδ), neuroblasts (PSA-NCAM, DCX, TUJ1), and an astrocyte marker (GFAP). Results were analyzed with non-parametric tests. We then studied correlations between the different markers and the percentage of phosphorylated TDP-43 (pTDP-43). RESULTS: We observed a statistically significant increase in proliferation in the SVZ in all patients with ALS. While this increase was more marked in ALS forms associated with dementia, the small sample size does not permit a statistical subgroup analysis. In contrast, proliferation in the SGZ was decreased in all patients. These alterations showed a positive and direct correlation with the percentage of pTDP-43 in the SVZ, and a negative, exponential correlation with that percentage in the SGZ. CONCLUSIONS: We observed alterations of the proliferation of neural progenitor in classic adult neurogenic niches in patients with ALS. The 2 neurogenic niches exhibited opposite changes such that proliferation increased in the SVZ and decreased in the SGZ.

Motoneuron Disease: Basic Science.

ALS is a relentless neurodegenerative disease in which motor neurons are the susceptible neuronal population. Their death results in progressive paresis of voluntary and respiratory muscles. The unprecedented rate of discoveries over the last two decades have broadened our knowledge of genetic causes and helped delineate molecular pathways. Here we critically review ALS epidemiology, genetics, pathogenic mechanisms, available animal models, and iPS cell technologies with a focus on their translational therapeutic potential. Despite limited clinical success in treatments to date, the new discoveries detailed here offer new models for uncovering disease mechanisms as well as novel strategies for intervention.

Motoneuron Disease: Clinical.

ALS is a neurodegenerative disease in which the primary symptoms result in progressive neuromuscular weakness. Recent studies have highlighted that there is significant heterogeneity with regard to anatomical and temporal disease progression. Importantly, more recent advances in genetics have revealed new causative genes to the disease. New efforts have focused on the development of biomarkers that could aid in diagnosis, prognosis, and serve as pharmacodynamics markers. Although traditional pharmaceuticals continue to undergo trials for ALS, new therapeutic strategies including stem cell transplantation studies, gene therapies, and antisense therapies targeting some of the familial forms of ALS are gaining momentum.

Rapidly progressive Fronto-temporal dementia (FTD) associated with Frontotemporal lobar degeneration (FTLD) in the presence of Fused in Sarcoma (FUS) protein: a rare, sporadic, and aggressive form of FTD.

Fronto-temporal dementia (FTD) associated with Fused in Sarcoma (FUS) protein accumulation is an uncommon cause of FTD with a distinct syndrome of young age onset behavioral variant FTD, without a family history of FTD and caudate atrophy. We present a sporadic case of a 61-year-old patient with mixed features of both behavioral variant FTD with later semantic language dissolution associated with pathologically proven FUS. He was older than usual for FUS pathology, his course was rapidly progressive, and he had atypical language features. This case broadens the clinical spectrum caused by FUS-protein-related FTD.

Behavioral variant frontotemporal dementia: advanced disease stages and death. A step to palliative care.

OBJECTIVE: The aim of the present study was to gain insight into the living and care situation in advanced behavioral variant frontotemporal dementia (bvFTD), to describe symptoms and findings in advanced bvFTD, and to evaluate somatic comorbidities and circumstances of death. METHODS: Standardized interviews were conducted with family caregivers of 83 patients with bvFTD. Forty-four percent of the patients were already deceased at the time of the interview. RESULTS: At the time of the interview or death, respectively, 47% of the patients lived in a nursing home. The median time between symptom onset and nursing home admission was 5.0 ± 5.5 years. In moderate and severe dementia stages almost all patients suffered from severe disabilities including impairment of language, gait, swallowing, and of the ability to care for themselves. Sixteen percent of the patients had got enteral tube feeding. Comorbid somatic diseases were diagnosed in 46% of the patients. Twenty-three percent of the deceased patients had been admitted into a hospital before death. Cardiovascular disease and respiratory disease, mostly pneumonia, were the most frequent causes of death. CONCLUSIONS: Advanced bvFTD is characterized by severe cognitive impairment and physical disabilities. BvFTD leads to a premature death. Our findings stress the importance of strategies that maximize patient comfort in advanced disease stages and allow for a peaceful death. Copyright © 2016 John Wiley & Sons, Ltd.

A linguagem na Demência Frontotemporal: uma análise à luz da Neurolinguística Enunciativo-Discursiva / Language in Frontotemporal Dementia: an analysis in light of Enunciative-Discursive Neurolinguistics

RESUMO Este estudo de caso objetiva analisar longitudinalmente a fala espontânea de um indivíduo com Demência Frontotemporal (DFT). Para isto, foram transcritos e analisados quatro episódios de terapia fonoaudiológica de um indivíduo com DFT entre 2012 e 2014 à luz da Neurolinguística Enunciativo-Discursiva. A análise evidenciou, ao longo da progressão da DFT, as diferentes estratégias semióticas utilizadas pelo indivíduo, como o uso discursivo da repetição e do gesto, bem como o lugar de importância do interlocutor para a promoção do fazer-dizer do indivíduo. Nesse sentido, conclui-se que o reconhecimento, na interlocução, das estratégias utilizadas pelo indivíduo em favor de sua posição de falante é o que viabiliza e legitima esta posição.

ABSTRACT The aim of this case study was to perform a cross-sectional analysis of spontaneous speech of a patient with Frontotemporal Dementia (FTD). For this purpose, four speech and language therapy episodes, from 2012 to 2014, were selected, transcribed and analyzed in light of Enunciative-Discursive Neurolinguistics. The analysis showed, as the patient's FTD status progressed, that he used different semiotic strategies, e.g., use of repetition and gesture during speech production. It also highlighted the importance of the interlocutor's role of prompting the patient to express verbal meaning. Thus, it can be concluded that the recognition of the strategies used by the patient in favor of his role as a speaker, during interactions, is what enables and legitimates his role.

Kraepelin's description of chronic mania: a clinical picture that meets the behavioral variant frontotemporal dementia phenotype.

Chronic mania is an under-investigated condition and few reports have associated this disorder with an organic background. The present work examines Kraepelin's reliable description of chronic mania from a current behavioral neurology viewpoint. Kraepelin had described a cluster of symptoms that are now recognized as core manifestations of the behavioral variant frontotemporal dementia (bvFTD) clinical phenotype. We also carried out additional reviews of original manuscripts from Kraepelin's peers, in order to find any case reports that might fulfill the current diagnostic proposal for bvFTD. Even though we failed to find an ideal case, we found some scholars who seemed to agree that chronic mania should be considered a special form of dementia. The present work highlights, through historical data, the possible overlapping features between primary psychiatric disorders and neuropsychiatric symptoms secondary to neurodegenerative conditions.

Kraepelin's description of chronic mania: a clinical picture that meets the behavioral variant frontotemporal dementia phenotype / A descrição de Kraepelin de mania crônica: um quadro clínico que corresponde ao fenótipo da variante comportamental da demência fronto-temporal

ABSTRACT Chronic mania is an under-investigated condition and few reports have associated this disorder with an organic background. The present work examines Kraepelin’s reliable description of chronic mania from a current behavioral neurology viewpoint. Kraepelin had described a cluster of symptoms that are now recognized as core manifestations of the behavioral variant frontotemporal dementia (bvFTD) clinical phenotype. We also carried out additional reviews of original manuscripts from Kraepelin’s peers, in order to find any case reports that might fulfill the current diagnostic proposal for bvFTD. Even though we failed to find an ideal case, we found some scholars who seemed to agree that chronic mania should be considered a special form of dementia. The present work highlights, through historical data, the possible overlapping features between primary psychiatric disorders and neuropsychiatric symptoms secondary to neurodegenerative conditions.

RESUMO A mania crônica constitui uma condição subinvestigada e alguns trabalhos têm associado esta desordem a um substrato orgânico. O presente manuscrito analisa a descrição fidedigna de Kraepelin de mania crônica a partir de um ponto de vista atual da neurologia comportamental. Concebemos que ele havia descrito um conjunto de sintomas que atualmente é reconhecido como manifestações centrais do fenótipo clínico da variante comportamental da demência frontotemporal (bvFTD). Também realizamos uma revisão adicional de manuscritos originais de pares contemporâneos de Kraepelin, a fim de procurar por um único relato de caso que poderia preencher critério diagnóstico atual de bvFTD. Mesmo que não tenhamos conseguido encontrar um caso perfeitamente exemplar, identificamos que alguns estudiosos da época pareciam concordar que a mania crônica devesse ser considerada uma forma especial de demência. O presente trabalho destaca por meio de dados históricos a sobreposição entre transtornos psiquiátricos primários e sintomas neuropsiquiátricos secundários a doenças neurodegenerativas.

A Case of Morvan Syndrome Mimicking Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.

INTRODUCTION: Morvan syndrome is a rare autoimmune/paraneoplastic disorder involving antibodies to the voltage-gated potassium channel complex. It is defined by subacute encephalopathy, neuromuscular hyperexcitability, dysautonomia, and sleep disturbance. It may present a diagnostic dilemma when trying to differentiate from amyotrophic lateral sclerosis with frontotemporal dementia. METHODS: A 76-year-old man with a history of untreated prostate adenocarcinoma was evaluated for subacute cognitive decline, diffuse muscle cramps, and hyponatremia. RESULTS: MRI demonstrated atrophy most prominent in the frontal and temporal regions. Electromyography (EMG) demonstrated diffuse myokymia/neuromyotonia. Polysomnography lacked REM and N3 sleep. Paraneoplastic panel detected antibodies to voltage-gated potassium channel complex (CASPR2 subtype). CONCLUSIONS: It is difficult to differentiate between Morvan syndrome and amyotrophic lateral sclerosis with frontotemporal dementia with examination and neuroimaging alone. There may be a link between Morvan syndrome and prostate adenocarcinoma which could help with screening/diagnosis. The authors found that laboratory and neurophysiological tests are indispensable in diagnosing and treating Morvan syndrome.

Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins.

The multiple roles played by RNA binding proteins in neurodegeneration have become apparent following the discovery of TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) involvement in amyotrophic lateral sclerosis and frontotemporal lobar dementia. In these two diseases, the majority of patients display the presence of aggregated forms of one of these proteins in their brains. The study of their functional properties currently represents a very promising target for developing the effective therapeutic options that are still lacking. This aim, however, must be preceded by an accurate evaluation of TDP-43 and FUS/TLS biological functions, both in physiological and disease conditions. Recent findings have uncovered several aspects of RNA metabolism that can be affected by misregulation of these two proteins. Progress has also been made in starting to understand how the aggregation of these proteins occurs and spreads from cell to cell. The aim of this review will be to provide a general overview of TDP-43 and FUS/TLS proteins and to highlight their physiological functions. At present, the emerging picture is that TDP-43 and FUS/TLS control several aspects of an mRNA's life, but they can also participate in DNA repair processes and in non-coding RNA metabolism. Although their regulatory activities are similar, they regulate mainly distinct RNA targets and show different pathogenetic mechanisms in amyotrophic lateral sclerosis/frontotemporal lobar dementia diseases. The identification of key events in these processes represents today the best chance of finding targetable options for therapeutic approaches that might actually make a difference at the clinical level. The two major RNA Binding Proteins involved in Amyotrophic Lateral Sclerosisi and Frontotemporal Dementia are TDP-43 and FUST/TLS. Both proteins are involved in regulating all aspects of RNA and RNA life cycle within neurons, from transcription, processing, and transport/stability to the formation of cytoplasmic and nuclear stress granules. For this reason, the aberrant aggregation of these factors during disease can impair multiple RNA metabolic pathways and eventually lead to neuronal death/inactivation. The purpose of this review is to provide an up-to-date perspective on what we know about this issue at the molecular level. This article is part of the Frontotemporal Dementia special issue.