Review: Somatic mutations in neurodegeneration

Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single‐cell sequencing, which can still be error‐prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late‐onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.     

Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer‐type pathology in the ageing brain

J. E. Simpson, P. G. Ince, L. J. Haynes, R. Theaker, C. Gelsthorpe, L. Baxter, G. Forster, G. L. Lace, P. J. Shaw, F. E. Matthews, G. M. Savva, C. Brayne and S. B. Wharton (2010) Neuropathology and Applied Neurobiology 36, 25–40
Population variation in oxidative stress and astrocyte DNA damage in relation to alzheimer‐type pathology in the ageing brain Aims: Increasing evidence suggests a role for oxidative damage to DNA in brain ageing and in neurodegenerative disorders, including Alzheimer's disease. Most studies have focussed on the reduced capacity for DNA repair by neurones, and have not taken into account the effect of oxidative stress on astrocytes, and their contribution to pathology. Methods: We examined levels of oxidative stress, DNA damage and DNA repair mechanisms in astrocytes in a population‐based sample derived from the Medical Research Council Cognitive Function and Ageing Neuropathology Study. Results: We demonstrate wide variation in parameters for oxidative stress and DNA damage in astrocytes in the ageing population. We show that there is a significant reduction (P = 0.002) in the lipid peroxidation marker malondialdehyde with increasing Braak stage in Alzheimer's disease. Furthermore, we demonstrate that expression of the DNA damage‐associated molecules H2AX and DNA‐dependent protein kinase do not increase with increasing Braak stage, rather there is evidence of a nonsignificant reduction in DNA‐dependent protein kinase expression by neurones and astrocytes, and in H2AX by neurones with increasing levels of Alzheimer's type pathology. Conclusions: These findings suggest that the changes in oxidative stress and the astrocyte DNA damage response are not accounted for as an accumulating effect due to established Alzheimer‐type pathology. We hypothesize that astrocyte damage, leading to impaired function, may contribute to the development of ageing brain pathology in some individuals.     

Review: The spectrum of clinical features seen with alpha synuclein pathology

It has been recognized for many years that a number of chronic neurodegenerative diseases of the CNS are characterized by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterized by this type of pathology – namely Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore at around this time, this same protein was also found within the glial inclusion bodies of patients dying with multiple system atrophy (MSA). These three disorders constitute the majority of patients with an ‘alpha synucleinopathy’, although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's disease (GD). In this review, we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD), as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology.     

Glycation in Parkinson's disease and Alzheimer's disease

Glycation is a spontaneous age‐dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α‐synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid β peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society     

Review: Astrocytes in Alzheimer's disease and other age‐associated dementias: a supporting player with a central role

Astrocytes have essential roles in the central nervous system and are also implicated in the pathogenesis of neurodegenerative disease. Forming non‐overlapping domains, astrocytes are highly complex cells. Immunohistochemistry to a variety of proteins can be used to study astrocytes in tissue, labelling different cellular components and sub‐populations, including glial fibrillary acidic protein, ALDH1L1, CD44, NDRG2 and amino acid transporters, but none of these labels the entire astrocyte population. Increasing heterogeneity is recognized in the astrocyte population, a complexity that is relevant both to their normal function and pathogenic roles. They are involved in neuronal support, as active components of the tripartite synapse and in cell interactions within the neurovascular unit (NVU), where they are essential for blood–brain barrier maintenance and neurovascular coupling. Astrocytes change with age, and their responses may modulate the cellular effects of neurodegenerative pathologies, which alone do not explain all of the variance in statistical models of neurodegenerative dementias. Astrocytes respond to both the neurofibrillary tangles and plaques of Alzheimer's disease, to hyperphosphorylated tau and Aβ, eliciting an effect which may be neuroprotective or deleterious. Not only astrocyte hypertrophy, in the form of gliosis, occurs, but also astrocyte injury and atrophy. Loss of normal astrocyte functions may contribute to reduced support for neurones and dysfunction of the NVU. Understanding how astrocytes contribute to dementia requires an understanding of the underlying heterogeneity of astrocyte populations, and the complexity of their responses to pathology. Enhancing the supportive and neuroprotective components of the astrocyte response has potential translational applications in therapeutic approaches to dementia.     

The VPS35 gene and Parkinson's disease

Parkinson's disease (PD), the second most common age‐related neurodegenerative disease, is characterized by loss of dopaminergic and nondopaminergic neurons, leading to a variety of motor and nonmotor symptoms. In addition to environmental factors, genetic predisposition and specific gene mutations have been shown to play an important role in the pathogenesis of this disorder. Recently, the identification of the vacuolar protein sorting 35 homolog gene (VPS35), linked to autosomal dominant late‐onset PD, has provided new clues to the pathogenesis of PD. Here we discuss the VPS35 gene, its protein function, and various pathways involved in Wnt/β‐catenin signaling and in the role of DMT1 mediating the uptake of iron and iron translocation from endosomes to the cytoplasm. Further understanding of these mechanisms will undoubtedly provide new insights into the pathogenic mechanisms of PD and may lead to prevention and better treatment of the disorder. © 2013 Movement Disorder Society     

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

Recent advances in cell reprogramming have enabled assessment of disease‐related cellular traits in patient‐derived somatic cells, thus providing a versatile platform for disease modeling and drug development. Given the limited access to vital human brain cells, this technology is especially relevant for neurodegenerative disorders such as Parkinson's disease (PD) as a tool to decipher underlying pathomechanisms. Importantly, recent progress in genome‐editing technologies has provided an ability to analyze isogenic induced pluripotent stem cell (iPSC) pairs that differ only in a single genetic change, thus allowing a thorough assessment of the molecular and cellular phenotypes that result from monogenetic risk factors. In this review, we summarize the current state of iPSC‐based modeling of PD with a focus on leucine‐rich repeat kinase 2 (LRRK2), one of the most prominent monogenetic risk factors for PD linked to both familial and idiopathic forms. The LRRK2 protein is a primarily cytosolic multi‐domain protein contributing to regulation of several pathways including autophagy, mitochondrial function, vesicle transport, nuclear architecture and cell morphology. We summarize iPSC‐based studies that contributed to improving our understanding of the function of LRRK2 and its variants in the context of PD etiopathology. These data, along with results obtained in our own studies, underscore the multifaceted role of LRRK2 in regulating cellular homeostasis on several levels, including proteostasis, mitochondrial dynamics and regulation of the cytoskeleton. Finally, we expound advantages and limitations of reprogramming technologies for disease modeling and drug development and provide an outlook on future challenges and expectations offered by this exciting technology.     

Hereditary chorea – what else to consider when the Huntington's disease genetics test is negative?

Chorea, cognitive, behavioural and psychiatric disturbance occur in varying combinations in Huntington's disease (HD). This is often easy to recognise particularly in the presence of an autosomal dominant history. Whilst HD may be the most common aetiology of such a presentation, several HD phenocopies should be considered if genetic testing for HD is negative. We searched PubMed and the Cochrane Database from January 1, 1946 up to January 1, 2016, combining the search terms: ‘chorea’, ‘Huntington's disease’, ‘HDL’ and ‘phenocopies’. HD phenocopies frequently display additional movement disorders such as myoclonus, dystonia, parkinsonism and tics. Here, we discuss the phenotypes, and investigations of HD‐like disorders where the combination of progressive chorea and cognitive impairment is obvious, but HD gene test result is negative. Conditions presenting with sudden onset chorea such as vascular, infectious and autoimmune causes are not the primary focus of our discussion, but we will make a passing reference to these as some of these conditions are potentially treatable. Hereditary forms of chorea are a heterogeneous group of conditions and this number is increasing. While most of these conditions are not curable, molecular genetic testing has enabled many of these disorders to be distinguished from HD. Getting a precise diagnosis may enable patients and their families to better understand the nature of their condition.     

Metabolic networks for assessment of therapy and diagnosis in Parkinson's disease

Neuroimaging and modern computational techniques like spatial covariance analysis have contributed greatly to the understanding of neural system abnormalities in neurodegenerative disorders such as Parkinson's disease (PD). The application of network analysis to metabolic PET data obtained from patients with PD has led to the identification and validation of two distinct spatial covariance patterns associated with the motor and cognitive manifestations of the disease. Quantifying the activity of these patterns in individual subjects has provided an objective tool for the assessment of treatment efficacy and differential diagnosis. We have found that activity of the PD motor‐related network is modulated by antiparkinsonian treatments such as dopaminergic therapy, deep brain stimulation (DBS), and subthalamic nucleus (STN) gene therapy. By contrast, the cognitive‐related network is not altered by these interventions for PD motor symptoms. This pattern may however change in response to therapies targeting the cognitive symptoms of this disorder. Recent work has focused on the identification of specific network biomarkers for atypical parkinsonian conditions such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). These disease‐related patterns can potentially be used in an automated imaging‐based algorithm to classify patients with these disorders. © 2009 Movement Disorder Society     

Hormetic approaches to the treatment of Parkinson's disease: Perspectives and possibilities

Age‐related changes in the brain reflect a dynamic interaction of genetic, epigenetic, phenotypic, and environmental factors that can be temporally restricted or more longitudinally present throughout the lifespan. Fundamental to these mechanisms is the capacity for physiological adaptation through modulation of diverse molecular and biochemical signaling occurring from the intracellular to the network‐systemic level throughout the brain. A number of agents that affect the onset and progression of Parkinson's disease (PD)‐like effects in experimental models exhibit temporal features, and mechanisms of hormetic dose responses. These findings have particular significance since the hormetic dose response describes the amplitude and range of potential therapeutic effects, thereby affecting the design and conduct of studies of interventions against PD (and other neurodegenerative diseases), and may also be important to a broader consideration of hormetic processes in resilient adaptive responses that might afford protection against the onset and/or progression of PD and related disorders.     

Synopsis on the Linkage of Alzheimer's and Parkinson's Disease with Chronic Diseases

Neurodegeneration is the progressive loss of neuronal structure and function, which ultimately leads to neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, and Huntington's disease. Even after the recent significant advances in neurobiology, the above‐mentioned disorders continue to haunt the global population. Several studies have suggested the role of specific environmental and genetic risk factors associated with these disorders. However, the exact mechanism associated with the progression of these disorders still needs to be elucidated. In the recent years, sophisticated research has revealed interesting association of prominent neurodegenerative disorders such as AD and PD with chronic diseases such as cancer, diabetes, and cardiovascular diseases. Several common molecular mechanisms such as generation of free radicals, oxidative DNA damage, aberrations in mitochondrial DNA, and dysregulation of apoptosis have been highlighted as possible points of connection. The present review summarizes the possible mechanism of coexistence of AD and PD with other chronic diseases.     

Environmental factors as modulators of neurodegeneration: Insights from gene–environment interactions in Huntington's disease

Unlike many other neurodegenerative diseases with established gene–environment interactions, Huntington's disease (HD) is viewed as a disorder governed by genetics. The cause of the disease is a highly penetrant tandem repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. In the year 2000, a pioneering study showed that the disease could be delayed in transgenic mice by enriched housing conditions. This review describes subsequent human and preclinical studies identifying environmental modulation of motor, cognitive, affective and other symptoms found in HD. Alongside the behavioral observations we also discuss potential mechanisms and the relevance to other neurodegenerative disorders, including Alzheimer's and Parkinson's disease. In mouse models of HD, increased sensorimotor and cognitive stimulation can delay or ameliorate various endophenotypes. Potential mechanisms include increased trophic support, synaptic plasticity, adult neurogenesis, and other forms of experience-dependent cellular plasticity. Subsequent clinical investigations support a role for lifetime activity levels in modulating the onset and progression of HD. Stress can accelerate memory and olfactory deficits and exacerbate cellular dysfunctions in HD mice. In the absence of effective treatments to slow the course of HD, environmental interventions offer feasible approaches to delay the disease, however further preclinical and human studies are needed in order to generate clinical recommendations. Environmental interventions could be combined with future pharmacological therapies and stimulate the identification of enviromimetics, drugs which mimic or enhance the beneficial effects of cognitive stimulation and physical activity.     

Copper in disorders with neurological symptoms: Alzheimer’s, Menkes, and Wilson diseases

Copper is an essential element for the activity of a number of physiologically important enzymes. Enzyme-related malfunctions may contribute to severe neurological symptoms and neurological diseases: copper is a component of cytochrome c oxidase, which catalyzes the reduction of oxygen to water, the essential step in cellular respiration. Copper is a cofactor of Cu/Zn-superoxide-dismutase which plays a key role in the cellular response to oxidative stress by scavenging reactive oxygen species. Furthermore, copper is a constituent of dopamine-β-hydroxylase, a critical enzyme in the catecholamine biosynthetic pathway. A detailed exploration of the biological importance and functional properties of proteins associated with neurological symptoms will have an important impact on understanding disease mechanisms and may accelerate development and testing of new therapeutic approaches. Copper binding proteins play important roles in the establishment and maintenance of metal-ion homeostasis, in deficiency disorders with neurological symptoms (Menkes disease, Wilson disease) and in neurodegenerative diseases (Alzheimer’s disease). The Menkes and Wilson proteins have been characterized as copper transporters and the amyloid precursor protein (APP) of Alzheimer’s disease has been proposed to work as a Cu(II) and/or Zn(II) transporter. Experimental, clinical and epidemiological observations in neurodegenerative disorders like Alzheimer’s disease and in the genetically inherited copper-dependent disorders Menkes and Wilson disease are summarized. This could provide a rationale for a link between severely dysregulated metal-ion homeostasis and the selective neuronal pathology.     

Prevalence and relation of dementia to various factors in Parkinson's disease

Aims: Parkinson's disease is a chronic neurodegenerative disorder characterized by bradykinesia, rigidity, and resting tremor. Dementia, among its non‐motor symptoms, is a debilitating complication affecting intellectual functioning. The aim of the present study was to determine the prevalence of dementia in Parkinson's disease and its relation to age, gender and stage of the disease. Methods: A retrospective chart analysis was performed on Parkinson's disease patients seen in a community‐based Parkinson's disease and movement disorder clinic between 2005 and 2010. Results: A total of 310 patients were included in this survey, among whom 61 patients (19.7%) with Parkinson's disease met the criteria for dementia. Age was found to be a significant factor in developing dementia, with 90% of patients with dementia aged ≥70. Gender, however, was not correlated with dementia in Parkinson's disease. On analysis of stage at which dementia developed, progression of the disease was positively correlated with prevalence of dementia. Conclusions: As age increases, the chances of developing dementia increase. Dementia, contrarily, is not selective between genders. The likelihood of developing dementia increases as the stage of disease advances. Further research is required in order to understand underlying mechanisms of dementia in Parkinson's disease.     

An overview of circulating cell-free microRNAs as putative biomarkers in Alzheimer's and Parkinson's Diseases

Circulating cell-free microRNAs (miRNAs) are stable in many biological fluids and their expression profiles can suffer changes under different physiological and pathological conditions. In the last few years, miRNAs have been proposed as putative noninvasive biomarkers in diagnosis, prognosis and response to treatment for several diseases, including neurodegenerative disorders as Alzheimer's disease (AD) and Parkinson's disease (PD). Cognitive and/or motor impairments are usually considered for establishing clinical diagnosis, and at this stage, the majority of the neurons may already be lost making difficult attempts of novel therapies. In this review, we intend to survey the circulating cell-free miRNAs found as dysregulated in cerebrospinal fluid, serum and plasma samples in AD and PD patients, and show how those miRNAs can be useful for early and differential diagnosis. Beyond that, we highlighted the miRNAs that are possibly related to common molecular mechanisms in the neurodegeneration process, as well those miRNAs related to specific disease pathways.     

The application of in vitro‐derived human neurons in neurodegenerative disease modeling

The development of safe and effective treatments for age‐associated neurodegenerative disorders is an on‐going challenge faced by the scientific field. Key to the development of such therapies is the appropriate selection of modeling systems in which to investigate disease mechanisms and to test candidate interventions. There are unique challenges in the development of representative laboratory models of neurodegenerative diseases, including the complexity of the human brain, the cumulative and variable contributions of genetic and environmental factors over the course of a lifetime, inability to culture human primary neurons, and critical central nervous system differences between small animal models and humans. While traditional rodent models have advanced our understanding of neurodegenerative disease mechanisms, key divergences such as the species‐specific genetic background can limit the application of animal models in many cases. Here we review in vitro human neuronal systems that employ stem cell and reprogramming technology and their application to a range of neurodegenerative diseases. Specifically, we compare human‐induced pluripotent stem cell‐derived neurons to directly converted, or transdifferentiated, induced neurons, as both model systems can take advantage of patient‐derived human tissue to produce neurons in culture. We present recent technical developments using these two modeling systems, as well as current limitations to these systems, with the aim of advancing investigation of neuropathogenic mechanisms using these models.     

Mitral cells and the glucagon‐like peptide 1 receptor: The sweet smell of success?

The olfactory bulb (OB) is often affected at very early stages of neurodegenerative disorders, in the so‐called “prodromal” phase. In Parkinson's disease (PD), olfactory disturbances appear years before motor symptoms arise. Additionally, pathological alpha‐synuclein aggregates are found in olfactory regions before spreading to other areas of the brain. Being positioned at the frontier between the brain and a potentially hostile environment, could explain the particular vulnerability of the OB. Mitral cells (MCs), the principal projecting neurons of the olfactory system, are involved in the pathogenesis and in the prion‐like progression of PD. They are affected by Lewy pathology and are thought to contribute to the axonal transport of misfolded alpha‐synuclein to other regions of the brain. Here, we first describe the main markers reported to distinguish MCs from other olfactory neurons. We focus on the glucagon‐like peptide 1 receptor (GLP‐1R), a membrane protein specifically expressed in MCs. After summarizing OB pathology, we explore the idea of targeting specifically MCs with GLP‐1 or its analogues. Exenatide has shown great promise as a neuroprotective and neurorestorative agent and has been used in a clinical trial for clinical PD. Since GLP‐1R activation has the ability to mitigate many facets of prodromal PD pathology, we postulate that once a robust biomarker is in place that is capable of identifying individuals in the prodromal phase of PD, homing in on GLP‐1R could assist in deferring, or eradicating to a significant degree, the clinical manifestation of this debilitating human disorder.