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Amyotrophic Lateral Sclerosis (ALS) is a fast progressive neurodegenerative disease characterized by muscle denervation, weakening and atrophy, which eventually culminates into death, mainly due to respiratory failure. The traditional view of ALS as a disorder affecting selectively motor neurons throughout the central nervous system has been progressively dispelled by innumerous lines of evidence indicating that other cells but motor neurons may be affected as well. Remarkably, this disorder is not limited to the motor system but rather configures as a systemic disease yielding a plethora of clinical signs. Among this broad clinical spectrum, sensory neuropathy occurring parallel to motor dysfunction is a quite frequent feature within ALS patients, which has spurred the interest of many investigators during the years. In line with this, morphological studies have confirmed that sensory neurons and axons' degeneration may occur in both ALS- experimental models and -patients. Noteworthy, this may have a nonetheless negligible role in ALS -related motor decline, as highlighted by recent studies showing that, degeneration of type I/II proprioceptive fibers is a primary source of alpha-motor neurons' death. These latter in fact, differently from gamma motor neurons, are a direct monosynaptic target of proprioceptive fibers. The present findings contribute to define a novel scenario of sensorimotor ALS pathophysiology where the gamma loop's fine connectivity may play a key role. In support to this view, in the present manuscript we provide a reappraisal on the role of single gamma loop's components in ALS.

Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons: compelling evidence points now towards additional involvement of extramotor functions. Beside the cognitive-behavioural disturbances, many ALS patients express extrapyramidal deficits: neuropathological findings fully support the multisystem brain degeneration. The therapeutical option to treat the multisystemic character of ALS represents an additional difficult task in absence of sensitive biomarkers or better understanding of the pathophysiological mechanisms of the disease. Future clinical trials need to identify subgroups of patients, representing the post-hoc analysis after a trial the extreme effort to define sensitive ALS patients to new treatments, as the edaravone story seems to demonstrate.

Neural progenitor cells (NPC) represent the stem-like niche of the central nervous system that maintains a regenerative potential also in the adult life. Despite NPC in the brain are well documented, the presence of NPC in the spinal cord has been controversial for a long time. This is due to a scarce activity of NPC within spinal cord, which also makes difficult their identification. The present review recapitulates the main experimental studies, which provided evidence for the occurrence of NPC within spinal cord, with a special emphasis on spinal cord injury and amyotrophic lateral sclerosis. By using experimental models, here we analyse the site-specificity, the phenotype and the main triggers of spinal cord NPC. Moreover, data are reported on the effect of specific neurogenic stimuli on these spinal cord NPC in an effort to comprehend the endogenous neurogenic potential of this stem cell niche.

Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disease clinically characterized by upper and lower motor neuron dysfunction resulting in rapidly progressive paralysis and death from respiratory failure. Most cases appear to be sporadic, but 5-10 % of cases have a family history of the disease, and over the last decade, identification of mutations in about 20 genes predisposing to these disorders has provided the means to better understand their pathogenesis. Next Generation sequencing (NGS) is an advanced high-throughput DNA sequencing technology which have rapidly contributed to an acceleration in the discovery of genetic risk factors for both familial and sporadic neurological and neurodegenerative diseases. These strategies allowed to rapidly identify disease-associated variants and genetic risk factors for both familial (fALS) and sporadic ALS (sALS), strongly contributing to the knowledge of the genetic architecture of ALS. Moreover, as the number of ALS genes grows, many of the proteins they encode are in intracellular processes shared with other known diseases, suggesting an overlapping of clinical and phatological features between different diseases. To emphasize this concept, the review focuses on genes coding for Valosin-containing protein (VPC) and two Heterogeneous nuclear RNA-binding proteins (HNRNPA1 and hnRNPA2B1), recently idefied through NGS, where different mutations have been associated in both ALS and other neurological and neurodegenerative diseases.

In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium administration during a long-lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the long-term treatment of spinal muscle atrophy.

The mechanisms underlying motoneuron degeneration in amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder that affects the motor system with progressive paralysis, are complex and not yet fully understood. It is generally agreed that ALS is a multifactorial and multisystem disease due not only possibly to genetic causes but also to other factors like oxidative stress, mitochondrial dysfunction, protein aggregation, RNA dysmetabolism, autophagy, and excitotoxicity glutamate-mediate. Altered oxidative stress biomarker profile has been repeatedly reported in ALS patients, which may suggest that abnormal free radical production is relevant in the ALS pathogenesis. This review aims to investigate how oxidative stress can affect other proposed mechanisms of neurodegeneration in ALS.

Although Parkinson's disease (PD) is diagnosed on the basis of motor symptoms, including slowness of movement, tremor, rigidity and difficulties with balance and walking, now we are aware that non-motor symptoms are highly prevalent, since they can anticipate motor symptoms and can cause severe consequences. Several studies have shown that non-motor symptoms, such as depression, anxiety and apathy, psychosis (e.g., hallucinations, delusions), sleep disturbance, and pain may have a greater adverse impact on quality of life and health economics compared with motor symptoms. Non-motor symptoms can be divided into four domains: neuropsychiatric (e.g., depression, anxiety, apathy, hallucinations, dementia), autonomic (e.g., constipation, orthostatic hypotension, urinary changes, sweating abnormalities), sleep (e.g., insomnia, sleep fragmentation, excessive daytime sleepiness, rapid eye movement, sleep behavioural disorder, restless leg syndrome), and sensory dysfunction (e.g., pain, olfactory dysfunction). This review addresses diagnosis and treatment of these disorders. The causative mechanisms remain complex, since they reflect the widespread brainstem and cortical pathology of PD, with involvement of several neurotransmitters, including dopamine (DA), serotonin, norepinephrine, and acetylcholine. The diagnosis is often challenging, especially for psychiatric disorders, and in particular affective disorders, because somatic features of psychopathology may overlap with the movement disorder itself. Treatments used are limited and psychiatric drugs may not be as effective as in general population. Evidence based medicine is quite poor and it still requires well-designed clinical studies.

"Striatal plasticity" is a term describing a variety of morphological and functional changes occurring both at pre- and post-synaptic level within the basal ganglia. In most cases striatal plasticity occurs when a loss of dopamine (DA) fibers in the striatum, in the course of Parkinsonism takes place. Plastic events include early pre-synaptic and long-term post-synaptic changes. In the context of long-term changes associated with striatal plasticity the role of intrinsic striatal catecholamine cells is emerging. This neuronal population expresses both tyrosine hydroxylase (TH) and DA transporter (DAT). These TH-positive cells are normally resident within the human caudate putamen but they dramatically increase during parkinsonism reaching an amount roughly corresponding to 50% of nigrostriatal neurons counted in control brains. This evidence led to hypothesize fascinating mechanisms bridging these neurons either with compensatory changes or the onset of aberrant behavioral activity. Very recently  the occurrence of these neurons was described during DA replacement therapy in parkinsonism, thus suggesting that these cells may represent the anatomical basis for plastic phenomena.  Thus, the present article, in the attempt to describe novel mechanisms generating striatal plasticity, details these cells in development and adult life and their potential role in maturation phenomena occurring in parkinsonism.

The present article aims to review state-of-the-art evidence of altered neurobiology and neuroanatomy underlyingpsychiatric symptoms in parkinsonism. This issue covers a wide range of symptoms encompassing anxiety, mooddisorders, psychosis as well as substance abuse and specific compulsive behaviors. Such a complex nosographymakes it impossible to deal with the neurobiology and neuroanatomy of each psychopathological condition perse, unless offering a trivial list of symptoms joined with brief explanations reporting potential causal mechanisms.This approach would only provide a rough synthesis of what previously reported without adding neither novelconcepts nor evidence to improve our insight into the neurobiology of parkinsonism as a psychiatric condition.Therefore, the analytical description of each psychiatric symptom associated with parkinsonism will be avoided butit will be referenced instead. In contrast, the present article will focus on the mechanisms why such a class of nonmotorsymptoms clusters in parkinsonian patients. In addition, we will seek to establish the relationship betweenthe occurrence of a given psychiatric condition and specific parkinsonian phenotypes. Again, an emphasis will begiven to the occurrence of behavioral fluctuations in parkinsonism where both motor and psychiatric symptomsmay possess a specific timing. The timing of these fluctuations will be related to the timing of dopamine substitutiontherapy and involvement of multiple neurotransmitters and brain regions as well. We provide evidence showingthat specific parkinsonian phenotypes (and genotypes) possess a widespread neuropathology, which in turn associatesto a fairly specific psychopathology. In contrast, other phenotypes (and genotypes) bring to very selectiveneuronal degeneration where the occurrence of psychiatric symptoms is rare if not absent at all. These clinicalpathological phenotypes associate with specific molecular mechanisms in the dynamics of neurobiology of disease.

Neurodegenerative diseases (NDs) include a large variety of disorders that affects specific areas of the centralnervous system, leading to psychiatric and movement pathologies. A common feature that characterizes thesedisorders is the neuronal formation and accumulation of misfolded protein aggregates that lead to cell death. Inparticular, different proteinaceous aggregates accumulate to trigger a variety of clinical manifestations: prionprotein (PrPSc) in prion diseases, β-amyloid (Aβ) in Alzheimer's disease (AD), α-synuclein in Parkinson's disease(PD), huntingtin in Huntington's disease (HD), superoxide dismutase and TDP-43 in amyotrophic lateral sclerosis(ALS), tau in tauopathies. Non-motor alterations also occur in several viscera, in particular the gastrointestinaltract. These often precede the onset of motor symptoms by several years. For this reason, dysautonomic changescan be predictive of NDs and their correct recognition is being assuming a remarkable importance. This peculiarfeature led more and more to the concept that neurodegeneration may initiate in the periphery and propagate retrogradelytowards the central nervous system in a prion-like manner. In recent years, a particular attention wasdedicated to the clinical assessment of autonomic disorders in patients affected by NDs. In this respect, experimentalanimal models have been developed to understand the neurobiology underlying these effects as well as toinvestigate autonomic changes in peripheral organs. This review summarizes experimental studies that have beencarried out to understand autonomic symptoms in NDs, with the purpose to provide appropriate tools for comprehensiveand integrated studies.

The neurobiology of non-motor symptoms in Parkinson's disease (PD) reveals a number of unexpected areas which once were not recognized a priori as part of the neuropathology underlying PD. These areas may belong either to central nervous system or periphery. Among central areas major efforts in the last decade led to recognize a number of brain nuclei as part of the disease spreading or disease onset in PD patients. Unexpectedly recent evidence deriving from pathological studies in PD patients and corroborated by experimental models of PD provided clear evidence that the spinal cord is often recruited in PD pathology. Such an involvement is intriguing since the major degenerative disease of the spinal cord (amyotrophic lateral sclerosis) features the involvement of dopaminergic neurons of the substantia nigra pars compacta, while some environmental (parkinsonism, ALS, and dementia of Guam) and genetic (Kufor-Rakeb syndrome) diseases are known to be characterized by mixed degeneration of pyramidal and extrapyramidal regions. Thus, the clear-cut between degeneration of dopaminergic neurons in the substantia nigra and the loss of pyramidal motor system appears now more as a continuum of   degeneration which converge in abnormal activity and cell pathology of motor neurons as a final common pathway. Among motor neurons, visceral efferent cells of the spinal cord are involved and provide a robust neurobiological findings which may justify a variety of non-motor autonomic symptoms which characterize PD. Neurodegeneration in the spinal cord extends to the dorsal horn of the grey matter posing an intriguing link between PD and sensory alterations. The present manuscript reviews the involvement of multiple regions of the spinal cord in PD and experimental parkinsonism in the attempt to provide both a neurobiological background to understand non motor symptoms and to provide the anatomical basis for disease spreading.

Analyzing non-motor symptoms in Parkinson's disease (PD) leads to critically re-define and update the disorder itself. The present Editorial encompasses epidemiological and clinical studies on PD patients joined with experimental findings to provide a novel definition of PD based on clinical, neuroanatomical and neurobiological findings.In fact, the plethora of symptoms described in PD patients are due to specific anatomical alterations which cluster in specific disease phenotypes. These PDs differ for disease onset and progression, disease severity and specific cluster of non-motor disturbances. Despite the variety of PD phenotypes, it is now well established that in almost all PD subgroups (except those autosomic recessive selective disorders exemplified by Parkin disease) a core anatomical defniition exists recruiting a variety of brainstem monoamine nuclei. Such a variety of PD pathologies can be defined as monoamine brainstem disorder (MBD).

Introducing ALS at present times leads to re-define the concept of motor neuron selectivity which characterizes this disorder. In fact, multiple systems including skin, liver, and bone marrow are altered in ALS patients. The motor neuron is still the focus of the disorder and the extended pathology did not modify the concept of ALS as a devastating disorder based on motor neuron loss. Nonetheless, the involvement of non-motor neurons as well as areas outside the central nervous system leads to a different perspective to understand the causes, pathophysiology and therapy of ALS. For this reason a specific issue is dedicated to understand whether intersecting basic, pre-clinical and clinical knowledge of ALS may lead to a coherent novel scenario allowing to translate basic findings into clinical practice. Several pre-clinical issues described in this volume appear robust enough to indicate that we should modify a number of approaches when designing future therapeutic strategies. Similarly, novel investigations based on altered cell to cell communication are needed to further progress in understanding amyotrophic lateral sclerosis.

Classic concepts on amyotrophic lateral sclerosis led to define the disease as a selective degeneration of upper and lower motor neurons. At present such selectivity is questioned by novel findings. For instance, the occurrence of frontotemporal dementia is now increasingly recognized in the course of ALS. Again, areas outside the central nervous system are targeted in ALS. In keeping with motor areas other cell types surrounding motor neurons such as glia and interneurons are key in the pathogenesis of ALS. This multiple cell involvement may be due to a prion-like diffusion of specific misfolded proteins which are altered in ALS. This is the case of FUS and TDP-43 which harbor a prion domain prone to pathological misfolding. These misfolded proteins are metabolized by the autophagy, but in ALS there is evidence for a specific deficit of autophagy which impedes the clearance of these proteins. These concepts lead to re-analyze the potential therapeutics of ALS. In fact, mere cell substitution (stem cell) therapy appears insufficient to contrast all the alterations in the various pathways affected by ALS. Although preclinical data speed the application of stem cells in human clinical trials, several hurdles limit their translation into new therapies. Future treatments are expected to consider the need to target both motor neurons and neighboring cells which may contribute to the diffusion and persistence of the disease. On this basis the present manuscript describes which future strategies need to be pursued in order to design optimal therapeutic trial in ALS.

Recent literature demonstrated that exposure to excitatory amino acid in specific experimental conditions might produce a defect in the autophagy pathway. Such an effect was observed in motor neurons exposed chronically to glutamate agonists. On the other hand, it is well known that glutamate induces motor neuron death and this is supposed to play a key role in the physiopathology of motor neuron loss in amyotrophic lateral sclerosis (ALS). Similarly, a defective recruitment of autophagy was recently documented in ALS. In the present study we found that exposure of motor neurons to kainic acid produces intracellular changes associated with defective autophagy. In this experimental conditions, pharmacological activation of autophagy rescues the loss of motor neurons.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration.

In the present review a large amount of experimental and clinical studies on ALS are discussed in an effort to dissect common pathogenic mechanisms which may provide novel information and potential therapeutic strategies for motor neuron degeneration.Protein clearing systems play a critical role in motor neuron survival during excitotoxic stress, aging and neurodegenerative disorders. Among various mechanisms which clear proteins from the cell recent studies indicate autophagy as the most prominent pathway to promote survival of motor neurons.Autophagy regulates the clearance of damaged mitochondria, endoplasmic reticulum and misfolded proteins in eukaryotic cells. Upon recruitment of the autophagy pathway, an autophagosome is produced and directed towards lysosomal degradation.Here we provide evidence that in both genetic and sporadic amyotrophic lateral sclerosis (ALS, the most common motor neuron disorder) a defect in the autophagy machinery is common. In fact, swollen, disrupted mitochondria and intracellular protein aggregates accumulate within affected motor neurons. These structures localize within double membrane vacuoles, autophagosomes, which typically cluster in perinuclear position. In keeping with this, when using autophagy inhibitors or suppressing autophagy promoting genes, motor symptoms and motor neuron death are accelerated. Conversely stimulation of autophagy alleviates motor neuron degeneration.Therefore, autophagy represents an important target when developing novel treatments in ALS.