Parkinson's disease (PD) is the second most common degenerative disorder. Although the disease was described more than 200 years ago, its pathogenetic mechanisms have not yet been fully described. In ...recent years, the discovery of the association between mutations of the
gene (encoding for the lysosomal enzyme glucocerebrosidase) and PD facilitated a better understating of this disorder.
mutations are the most common genetic risk factor of the disease. However, mutations of this gene can be found in different phenotypes, such as Gaucher's disease (GD), PD, dementia with Lewy bodies (DLB) and rapid eye movements (REM) sleep behavior disorders (RBDs). Understanding the pathogenic role of this mutation and its different manifestations is crucial for geneticists and scientists to guide their research and to select proper cohorts of patients. Moreover, knowing the implications of the
mutation in the context of PD and the other associated phenotypes is also important for clinicians to properly counsel their patients and to implement their care. With the present review we aim to describe the genetic, clinical, and therapeutic features related to the mutation of the
gene.
Although the pathogenesis of neurodegenerative diseases is still widely unclear, various mechanisms have been proposed and several pieces of evidence are supportive for an important role of ...mitochondrial dysfunction. The present review provides a comprehensive and up-to-date overview about the role of mitochondria in the two most common neurodegenerative disorders: Alzheimer’s disease (AD) and Parkinson’s disease (PD). Mitochondrial involvement in AD is supported by clinical features like reduced glucose and oxygen brain metabolism and by numerous microscopic and molecular findings, including altered mitochondrial morphology, impaired respiratory chain function, and altered mitochondrial DNA. Furthermore, amyloid pathology and mitochondrial dysfunction seem to be bi-directionally correlated. Mitochondria have an even more remarkable role in PD. Several hints show that respiratory chain activity, in particular complex I, is impaired in the disease. Mitochondrial DNA alterations, involving deletions, point mutations, depletion, and altered maintenance, have been described. Mutations in genes directly implicated in mitochondrial functioning (like Parkin and PINK1) are responsible for rare genetic forms of the disease. A close connection between alpha-synuclein accumulation and mitochondrial dysfunction has been observed. Finally, mitochondria are involved also in atypical parkinsonisms, in particular multiple system atrophy. The available knowledge is still not sufficient to clearly state whether mitochondrial dysfunction plays a primary role in the very initial stages of these diseases or is secondary to other phenomena. However, the presented data strongly support the hypothesis that whatever the initial cause of neurodegeneration is, mitochondrial impairment has a critical role in maintaining and fostering the neurodegenerative process.
Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained ...hyperferritinemia. Their findings suggested the existence of an autosomal-recessive disorder. We carried out whole-exome sequencing to detect the genetic cause of hyperferritinemia. Immunohistochemistry and flow cytometry assays were performed on liver biopsies and monocyte-macrophages to confirm the pathogenic role of the identified candidate variants. Through a combined approach of whole-exome sequencing and homozygosity mapping, we found bi-allelic STAB1 variants in ten subjects from seven families. STAB1 encodes the multifunctional scavenger receptor stabilin-1. Immunohistochemistry and flow cytometry analyses showed absent or markedly reduced stabilin-1 in liver samples, monocytes, and monocyte-derived macrophages. Our findings show a strong association between otherwise unexplained hyperferritinemia and bi-allelic STAB1 mutations suggesting the existence of another genetic cause of hyperferritinemia without iron overload and an unexpected function of stabilin-1 in ferritin metabolism.
Background
Freezing of gait (FOG) is a disabling motor symptom occurring mainly in the advanced stage of Parkinson’s disease (PD).
Methods
This review outlines the clinical manifestation of FOG and ...its relationship with levodopa treatment, the differential diagnosis with respect to other neurodegenerative and secondary forms and the available treatment.
Results
We report the proposed models explaining the FOG phenomenon and summarize the available knowledge on FOG etiology’s potential genetic contribution. A complete understanding of the mechanisms underlying FOG in PD is essential to find the best therapy. Different treatment options exist but are still not entirely successful, and often a combination of approaches is needed.
Conclusions
Further studies focusing on the potential genetic role in FOG may increase the knowledge on the FOG etiology and pathophysiology, allowing further individualized treatment strategies for this very disabling phenomenon.
Abstract
In the ongoing process of uncovering molecular abnormalities in neurodegenerative diseases characterized by toxic protein aggregates, nucleo-cytoplasmic transport defects have an emerging ...role. Several pieces of evidence suggest a link between neuronal protein inclusions and nuclear pore complex (NPC) damage. These processes lead to oxidative stress, inefficient transcription, and aberrant DNA/RNA maintenance. The clinical and neuropathological spectrum of NPC defects is broad, ranging from physiological aging to a suite of neurodegenerative diseases. A better understanding of the shared pathways among these conditions may represent a significant step toward dissecting their underlying molecular mechanisms, opening the way to a real possibility of identifying common therapeutic targets.
Syndromes associated with multiple mtDNA deletions are due to different molecular defects that can result in a wide spectrum of predominantly adult-onset clinical presentations, ranging from ...progressive external ophthalmoplegia (PEO) to multisystemic disorders of variable severity. The autosomal-dominant form of PEO is genetically heterogeneous. Recently, causative mutations have been reported in several nuclear genes that encode proteins of the mtDNA replisome machinery (POLG, POLG2, and C10orf2) or that are involved in pathways for the synthesis of deoxyribonuclotides (ANT1 and RRM2B). Despite these findings, putative mutations remain unknown in half of the subjects with PEO. We report the identification, by exome sequencing, of mutations in DNA2 in adult-onset individuals with a form of mitochondrial myopathy featuring instability of muscle mtDNA. DNA2 encodes a helicase/nuclease family member that is most likely involved in mtDNA replication, as well as in the long-patch base-excision repair (LP-BER) pathway. In vitro biochemical analysis of purified mutant proteins revealed a severe impairment of nuclease, helicase, and ATPase activities. These results implicate human DNA2 and the LP-BER pathway in the pathogenesis of adult-onset disorders of mtDNA maintenance.
Transcranial direct current stimulation (tDCS) is a non-invasive technique for inducing prolonged functional changes in the human cerebral cortex. This simple and safe neurostimulation technique for ...modulating motor functions in Parkinson’s disease could extend treatment option for patients with movement disorders. We assessed whether tDCS applied daily over the cerebellum (cerebellar tDCS) and motor cortex (M1-tDCS) improves motor and cognitive symptoms and levodopa-induced dyskinesias in patients with Parkinson’s disease (PD). Nine patients (aged 60–85 years; four women; Hoehn & Yahr scale score 2–3) diagnosed as having idiopathic PD were recruited. To evaluate how tDCS (cerebellar tDCS or M1-tDCS) affects motor and cognitive function in PD, we delivered bilateral anodal (2 mA, 20 min, five consecutive days) and sham tDCS, in random order, in three separate experimental sessions held at least 1 month apart. In each session, as outcome variables, patients underwent the Unified Parkinson’s Disease Rating Scale (UPDRS III and IV) and cognitive testing before treatment (baseline), when treatment ended on day 5 (T1), 1 week later (T2), and then 4 weeks later (T3), at the same time each day. After patients received anodal cerebellar tDCS and M1-tDCS for five days, the UPDRS IV (dyskinesias section) improved (
p
< 0.001). Conversely, sham tDCS, cerebellar tDCS, and M1-tDCS left the other variables studied unchanged (
p
> 0.05). Despite the small sample size, our preliminary results show that anodal tDCS applied for five consecutive days over the motor cortical areas and cerebellum improves parkinsonian patients’ levodopa-induced dyskinesias.
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