Non-motor Functions Research Articles

Trajectories of Prediagnostic Motor and Non-Motor Functioning in Parkinson Disease (I1.004)

Trajectories of Prediagnostic Motor and Non-Motor Functioning in Parkinson Disease (I1.004)

Clinical study of the mentation, behavior and mood disorders in Parkinson’s disease

Introduction: Parkinson's disease is a general invalidating neurodegenerative disease. The impaired non-motor functions are well recognized as part of the clinical course of the disease with great impact over the quality of life of the patients. On the other hand, they are highly unrecognized by clinicians and pose great difficulty in detection and measurement. The UPDRS is widely used to assess and follow up PD patients and Part I is used to assess non motor functions such as mentation, behavior and mood disorders. Therefore, we used it in our study for the assessment of the prevalence of the non-motor symptoms measured by UPDRS Part I in PD patients. Objective: To show that there's high prevalence of mentation, behavior and mood disorders as measured by UPDRS Part I in PD patients. Methods: 293 patients with Parkinson's disease (129 men and 164 women) aged 58-79, randomly picked for an 8-year period (2005-2012) were studied. The study used the following assessment tools: І. Unified Parkinson's Disease Rating Scale; Modified Hoehn and Yahr scale for assessment of clinical symptoms; Schwab and England Activities of Daily Living Scale. Statistical methods for processing the data received – SPSS statistics software with analysis of variances and alternates was used. Results: The mentation, behavior and mood functions were studied in 293 patients diagnosed with Parkinson's disease. Lack of motivation/initiative was most frequently observed – in 245 patients (83.6%), followed by depression – in 200 patients (68.2%)and memory disorders – in 199 patients (67.9%). Thought disorder was the least frequent (26.9%). As a result of these disorders all patients had a considerably reduced quality of life mainly due to the development of significant cognitive impairment. Conclusion: This results confirm the observation that mentation, behavior and mood dysfunctions are a highly prevalent and important feature of PD. Therefore, treating physicians should look for them routinely. The UPDRS showed that it is sensitive and reliable tool for detecting such symptomatology.

Nonmotor Functions of the Cerebellum: An Introduction.

The concept of nonmotor functions of the cerebellum (little cerebrum)[1][1] is an intriguing proposal that has garnered little attention in the past but has become a relatively recent focal point for neuroscience investigators. The preponderance of anatomic and clinical evidence supporting the

Editorial: Fatigue in Multiple Sclerosis

Editorial: Fatigue in Multiple Sclerosis

Randomized controlled expressive writing pilot in individuals with Parkinson's disease and their caregivers.

BackgroundIndividuals with Parkinson’s disease (PD) and their caregivers are at risk for emotional distress and hypercortisolism. Expressive writing is an effective complementary intervention to ameliorate the psychological and physiological effects of chronic illness. This pilot study aimed to evaluate feasibility and preliminary effectiveness of an expressive writing intervention for individuals with PD and their caregivers.MethodsIndividuals with PD (N = 27) and their caregivers (N = 14) were randomly assigned to expressive (N = 15 patients, eight caregivers) or neutral (N = 12 patients, six caregivers) writing conditions. Cortisol awakening response (CAR), non-motor functioning, quality of life, and performance on tests of cognitive functioning were assessed at baseline, immediate post, 4-month, and 10-month post intervention.ResultsAttrition was a challenge as eight patients (29.62 %) and four caregivers (28.57 %) chose to discontinue before beginning the intervention or were lost to follow up prior to completing the intervention or the first follow up visit. Significant reduction in anxiety, marginally significant improvement in depression and caregiver burden, and significant improvements in performance on tests of learning and memory were observed, but these changes did not differ by writing condition. CAR significantly differed over time between patients and caregivers and writing conditions.ConclusionsSome evidence for the feasibility and effectiveness of writing to alleviate hypercortisolism was demonstrated in a small sample of PD patients; however, relatively high attrition rates and the lack of difference between expressive and neutral writing conditions on emotional and neurocognitive outcomes suggests expressive writing procedure modifications may be needed to obtain optimal results for this population.Trial registrationClinicalTrials.gov, NCT02217735, Study Start Date: August 30, 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s40359-015-0101-4) contains supplementary material, which is available to authorized users.

The impact of combined administration of paraquat and maneb on motor and non-motor functions in the rat

Paraquat (PQ) and maneb (MB) are potential risk factors for Parkinson’s disease. However, their impact on non-motor disorders, monoamine neurotransmission and basal ganglia function is not clearly determined. Here we investigated the effects of combined treatment with PQ/MB on motor behavior, anxiety and “depressive-like” disorders, tissue content of monoamines, and subthalamic nucleus (STN) neuronal activity. Male Sprague–Dawley rats were intoxicated by PQ (10mg/kg) and MB (30mg/kg) twice a week. Two weeks later, the majority of animals (group 1, 16/26) showed a severe loss of body weight with tremor and respiratory distress and others (group 2, 6/26) showed only tremor. Animals of group 2 received PQ/MB during four weeks before developing weight loss. A last group (group 3, 4/26) was insensitive to PQ/MB after 6weeks of injections. Groups 1 and 2 displayed a failure of motor activity and motor coordination. Group 3 showed slight motor deficits only after the last injection of PQ/MB. Moreover, PQ/MB induced anxiety and “depressive-like” behaviors in animals of groups 2 and 3. Biochemical analysis showed that PQ/MB reduced striatal dopamine (DA) tissue content paralleled by changes in the activity of STN neurons without changing the content of norepinephrine and serotonin in the cortex. Our data provide evidence that individuals are not equally sensitive to PQ/MB and show that the motor deficits in vulnerable animals, are not only a result of DA neuron degeneration, but may also be a consequence of peripheral disabilities. Nevertheless, the parkinsonian-like non-motor impairments may be a direct consequence of the bilateral DA depletion.

The Parkinson's Disease-Associated Mutation LRRK2-G2019S Impairs Synaptic Plasticity in Mouse Hippocampus.

Parkinson's disease (PD) is among the most common neurological diseases and is best known for its adverse effects on brain regions that control motor function, resulting in tremor, rigidity, and gait abnormalities. Less well appreciated are the psychiatric symptoms experienced by many PD patients, including depression and memory loss, which do not respond well to currently available treatments for PD. Here, we describe functional effects of a common PD-linked mutation of leucine-rich repeat kinase 2 in the mouse hippocampus, an area of the brain that is responsible for encoding and retaining memories. By providing a potential mechanism for some of the cognitive symptoms produced by this mutation, our findings may lead to novel approaches for the treatment of nonmotor symptoms of PD.

Cerebellar Nonmotor Functions – Approaches and Significance

The cerebellum is involved in the control of motor and nonmotor functions. Refined and innovative experimental and clinical approaches, starting from anatomy and including functional magnetic resonance imaging (fMRI), have allowed researchers to store extensive information on the cerebellar contributions to motor control and also helped them to understanding cerebellar nonmotor functions. Does the cerebellum process exclusively cerebral information related to certain specificactions, or does it also process some forms of information independent of such relation? At present, researchers are close to evaluating how the cerebellum is active during resolution of cognitive tasks. Various therapy lines in perspective, from cerebellar stimulation to cerbellar grafts and artificial cerebellum, are of particular significance, as they can restore lost brain functions in animal models and repair in sufficient brain processes in patients.

Individual differences in resting-state functional connectivity with the executive network: support for a cerebellar role in anxiety vulnerability.

This study characterized cerebellar connectivity with executive intrinsic functional connectivity networks. Using seed regions at the right and left dorsolateral prefrontal cortices (dlPFC) and right orbital frontoinsula, we measured resting-state brain connectivity in healthy college-aged participants. Based on the previous research demonstrating a relationship between the cerebellum and self-report measures of behavioral inhibition, we assessed individual differences in connectivity between groups. Overall, intrinsic activity in cerebellar lobule VIII was significantly correlated with the executive network and cerebellar Crus I with the salience network. Between-group comparisons indicated stronger cerebellar connectivity with the executive network in behaviorally inhibited individuals. Intrinsic activity in Crus I, a region previously implicated in non-motor cerebellar functions, significantly correlated with intrinsic activity in the right dlPFC seed region. These findings support a growing number of studies demonstrating cerebellar influence on higher cognitive processes, extending this relationship to individual differences in anxiety vulnerability.

Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats

The dorsolateral striatum (DLS) processes motor and non-motor functions and undergoes extensive dopaminergic degeneration in Parkinson's disease (PD). The nigrostriatal dopaminergic degeneration also affects other brain areas including the pre-frontal cortex (PFC), which has been associated with the appearance of anhedonia and depression at pre-motor phases of PD. Using behavioral, neurochemical, and electrophysiological approaches, we investigated the temporal dissociation between the role of the DLS and PFC in the appearance of anhedonia and defense behaviors relevant to depression in rats submitted to bilateral DLS lesions with 6-hydroxydopamine (6-OHDA; 10μg/hemisphere). 6-OHDA induced partial dopaminergic nigrostriatal damage with no gross motor impairments. Anhedonic-like behaviors were observed in the splash and sucrose consumption tests only 7days after 6-OHDA lesion. By contrast, defense behaviors relevant to depression evaluated in the forced swimming test and social withdrawal only emerged 21days after 6-OHDA lesion when anhedonia was no longer present. These temporally dissociated behavioral alterations were coupled to temporal- and structure-dependent alterations in dopaminergic markers such as dopamine D1 and D2 receptors and dopamine transporter, leading to altered dopamine sensitivity in DLS and PFC circuits, evaluated electrophysiologically. These results provide the first demonstration of a dissociated involvement of the DLS and PFC in anhedonic-like and defense behaviors relevant to depression in 6-OHDA-lesioned rats, which was linked with temporal fluctuations in dopaminergic receptor density, leading to altered dopaminergic system sensitivity in these two brain structures. This sheds new light to the duality between depressive and anhedonic symptoms in PD.

The Vestibular System: A Newly Identified Regulator of Bone Homeostasis Acting Through the Sympathetic Nervous System.

The vestibular system is a small bilateral structure located in the inner ear, known as the organ of balance and spatial orientation. It senses head orientation and motion, as well as body motion in the three dimensions of our environment. It is also involved in non-motor functions such as postural control of blood pressure. These regulations are mediated via anatomical projections from vestibular nuclei to brainstem autonomic centers and are involved in the maintenance of cardiovascular function via sympathetic nerves. Age-associated dysfunction of the vestibular organ contributes to an increased incidence of falls, whereas muscle atrophy, reduced physical activity, cellular aging, and gonadal deficiency contribute to bone loss. Recent studies in rodents suggest that vestibular dysfunction might also alter bone remodeling and mass more directly, by affecting the outflow of sympathetic nervous signals to the skeleton and other tissues. This review will summarize the findings supporting the influence of vestibular signals on bone homeostasis, and the potential clinical relevance of these findings.

Strengths and challenges faced by school-aged children with unilateral CP described by the Five To Fifteen parental questionnaire

Purpose: The purpose of this study was to describe motor and non-motor (e.g. cognitive, social, and behavioral) challenges faced in daily life by children with unilateral cerebral palsy (UCP). Methods: In this cross-sectional study, parents completed the Five to Fifteen questionnaire and provided demographic information for 46 children aged 6–15 years (mean 11.01 ± 2.89 SD). Results: Most children were reported to have problems in both motor and non-motor domains, ranging from 20 to 92% depending on the domain. Perception and learning were the non-motor functions most commonly reported as challenging (63 and 65%, respectively). The total number of problems was significantly higher in age groups above 9 years. The correlation between all domains was high, but was consistently higher with the fine motor sub-domain, which could be used to predict executive function, perception, memory, and learning outcomes (R2=0.502, 0.642, 0.192, 0.192). Conclusion: Most children with CP have everyday challenges beyond their primary motor deficiencies.

Aberrant cerebellar connectivity in motor and association networks in schizophrenia.

Schizophrenia is a devastating illness characterized by disturbances in multiple domains. The cerebellum is involved in both motor and non-motor functions, and the “cognitive dysmetria” and “dysmetria of thought” models propose that abnormalities of the cerebellum may contribute to schizophrenia signs and symptoms. The cerebellum and cerebral cortex are reciprocally connected via a modular, closed-loop network architecture, but few schizophrenia neuroimaging studies have taken into account the topographical and functional heterogeneity of the cerebellum. In this study, using a previously defined 17-network cerebral cortical parcellation system as the basis for our functional connectivity seeds, we systematically investigated connectivity abnormalities within the cerebellum of 44 schizophrenia patients and 28 healthy control participants. We found selective alterations in cerebro-cerebellar functional connectivity. Specifically, schizophrenia patients showed decreased cerebro-cerebellar functional connectivity in higher level association networks (ventral attention, salience, control, and default mode networks) relative to healthy control participants. Schizophrenia patients also showed increased cerebro-cerebellar connectivity in somatomotor and default mode networks, with the latter showing no overlap with the regions found to be hypoconnected within the same default mode network. Finally, we found evidence to suggest that somatomotor and default mode networks may be inappropriately linked in schizophrenia. The relationship of these dysconnectivities to schizophrenia symptoms, such as neurological soft signs and altered sense of agency, is discussed. We conclude that the cerebellum ought to be considered for analysis in all future studies of network abnormalities in SZ, and further suggest the cerebellum as a potential target for further elucidation, and possibly treatment, of the underlying mechanisms and network abnormalities producing symptoms of schizophrenia.

Selective dysfunction of basal ganglia subterritories: From movement to behavioral disorders.

Historically, Parkinson's disease (PD) was defined as a pure movement disorder. Currently, it is widely accepted that this disease is also characterized by nonmotor signs, such as depression, apathy, and anxiety. On the other hand, the consideration of Gilles de la Tourette syndrome (GTS) as a neuropsychiatric disorder has also been debated. In this review, we will focus on these two disorders, which combine both motor and behavioral features and in which dysfunction of cortical and subcortical regions was suggested. Anatomical, experimental, and clinical data are reported to support the involvement of basal ganglia (BG) in cognitive and motivational functions in addition to motor control. In PD, the nonmotor signs could result from the heterogeneity of dopaminergic lesions and excessive activation of the dopamine receptors, particularly within the limbic neuronal networks. Experimental results obtained on nonhuman primates using local disinhibition within functional territories of BG allowed the precise mapping of their motor and nonmotor functions. Thus, impairment of inhibitory control inside specific striatal territories induced behavioral disorders and abnormal movements, which had striking similarities to clinical expressions of GTS. Establishing such a relationship between BG subterritories and motor and behavioral disorders could potentially be helpful for future target choices for DBS in many neuropsychiatric disorders. Furthermore, it is also of great interest for therapeutic research and for the efficient targeting of symptom relief to determine the precise pharmacological effects of the two main modulators of BG function, which are dopamine and serotonin.

Abstract 144: Forced Aerobic Exercise Enhances Upper Extremity Task Practice in Patients with Stroke

Introduction: Aerobic exercise (AE) has been shown to improve cardiovascular health in individuals with stroke; however, the potential role of AE in enhancing neuroplasticity after stroke has not been systematically studied. We have implemented a forced exercise (FE) cycling intervention, initially developed for individuals with Parkinson’s disease, with a cohort of individuals with chronic stroke. We hypothesize that intensive AE training, when paired with repetitive task practice (RTP), will “prime” the central nervous system, to exploit the motor learning effects of task practice. Hypothesis: Individuals who perform FE followed by RTP will demonstrate greater improvements in motor and non-motor function compared to the voluntary rate aerobic exercise (VE) + RTP and RTP only groups. Individuals in both AE groups (FE and VE) will demonstrate greater improvements in VO2peak compared to the RTP only group. Methods: Fifteen individuals 6-12 months post-stroke were enrolled into one of the following groups: 1) Forced Exercise + RTP (FE + RTP); 2) Voluntary Exercise + RTP (VE + RTP); and 3) Time-matched RTP. Participants in the AE groups completed one 45-minute session of stationary cycling followed immediately by one 45-minute session of upper extremity RTP; however, the rate of cycling for the FE group was augmented to approximately 35% faster than their voluntary rate. All participants completed a total of 24 exercise sessions over an 8-week period. Results: While all three groups made significant improvements in motor function as measured by the Fugl-Meyer Assessment (p=.03), the FE+RTP group exceeded the VE+RTP and RTP only groups, approaching statistical significance (p=0.06), despite the two AE groups completing 44% less RTP practice time than the RTP group. Improvements in self-reported quality of life and depressive symptomology also improved across all three groups, with trends favoring the FE group. VO2peak improved by 1.1 and 2.68 mL/kg/min for the FE+RTP and VE+RTP groups, respectively; while VO2peak decreased by 0.85mL/kg/min in the RTP group. Conclusion: FE + RTP is a promising intervention to enhance motor and non-motor function, in addition to aerobic capacity in individuals 6-12 months after stroke.

Cellular commitment in the developing cerebellum.

The mammalian cerebellum is located in the posterior cranial fossa and is critical for motor coordination and non-motor functions including cognitive and emotional processes. The anatomical structure of cerebellum is distinct with a three-layered cortex. During development, neurogenesis and fate decisions of cerebellar primordium cells are orchestrated through tightly controlled molecular events involving multiple genetic pathways. In this review, we will highlight the anatomical structure of human and mouse cerebellum, the cellular composition of developing cerebellum, and the underlying gene expression programs involved in cell fate commitments in the cerebellum. A critical evaluation of the cell death literature suggests that apoptosis occurs in ~5% of cerebellar cells, most shortly after mitosis. Apoptosis and cellular autophagy likely play significant roles in cerebellar development, we provide a comprehensive discussion of their role in cerebellar development and organization. We also address the possible function of unfolded protein response in regulation of cerebellar neurogenesis. We discuss recent advancements in understanding the epigenetic signature of cerebellar compartments and possible connections between DNA methylation, microRNAs and cerebellar neurodegeneration. Finally, we discuss genetic diseases associated with cerebellar dysfunction and their role in the aging cerebellum.

Effects of treadmill exercise on hippocampal neurogenesis in an MPTP /probenecid-induced Parkinson's disease mouse model.

[Purpose] This study aimed to investigate the effect of treadmill exercise on non-motor function, specifically long-term memory, in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-induced Parkinson’s disease mouse model. [Methods] A mouse model of Parkinson’s disease was developed by injecting 20 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 250 mg/kg of probenecid (P). We divided in into four groups: probenecid group, probenecid-exercise group, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group. Mice in the exercise groups ran on treadmill for 30 min/day, five times per week for 4 weeks. [Results] Latency in the passive avoidance test increased in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group. In addition, the number of 5-bromo-2-deoxyuridine/NeuN-positive cells and 5-bromo-2-deoxyuridine/doublecortin-positive cells in the hippocampal dentate gyrus was higher in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group than that in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group. These changes were associated with the expression of brain-derived neurotrophic factor in the hippocampus. [Conclusion] Our results suggest that treadmill exercise may improve long-term memory in Parkinson’s disease mice by facilitating neurogenesis via increased expression of neurotrophic factors.

Advances from probabilistic tractography in connections of the limbic system with the cerebellum

The limbic system is a complex set of brain structures located on both sides of the thalamus, right under the cerebrum. It is not a separate system but a collection of structures from the telencephalon, diencephalon, and mesencephalon, including the hippocampus, amygdala, anterior thalamic nuclei, fornix, columns of fornix, mammillary body, septum pellucidum, habenular commissure, cingulate gyrus, parahippocampal gyrus, limbic cortex, pars of olfactory system and limbic midbrain areas. Nevertheless, recent studies showed that the definition of anatomical structures considered part of the limbic system is a controversial subject. Although the role of the cerebellum was traditionally considered mainly associated to motion control, it has been recently suggested a cerebellar involvement in emotions control, cognitive processes and social behavior. In this regard, we have previously demonstrated that the cerebellum is interconnected with the hippocampus [1]. In this work, a wider sample of normal subjects was examined by using probabilistic Constrained Spherical Deconvolution (CSD) tractography, which represents a method able to overcome many limitations of other Diffusion Tensor Imaging (DTI) techniques, providing more accurate data [2]. We found evidences in the human brain that the cerebellum is widely linked with limbic-related structures and provided a more reliable demonstration of direct cerebello-limbic pathways. In addition, we further extendend our analysis to the other limbic connections including uncinated fasciculus, cingulate fasciculus, inferior longitudinal fasciculus, anterior thalamic connections and fornix. Although these pathways have been already described in the tractographic literature we provided reconstruction and quantitative analysis, which could be potentially useful to explore pathological conditions damaging this system. Finally, the demonstration of the existence of cerebello-limbic connections could constitute an important step in the knowledge of the anatomic substrate of non-motor cerebellar functions.

Effects of an adapted physical activity program on motor and non-motor functions and quality of life in patients with Parkinson's disease.

Several studies have clearly shown that strategies of health promotion, such as fitness and general exercise programs, may improve quality of life (QoL), motor and non-motor functions in Parkinson's disease (PD) patients. However, little is known about the effects of specific Adapted Physical Activity (APA) programs on PD patients. To determine the effects of an APA program on motor and non-motor symptoms, functional performances and QoL in PD patients. Nine consecutive PD patients (5 men, 4 women, 64.4 ± 6.8 years) able to ambulate independently (Hoehn and Yahr: from stage 1 to 3) and not demented, were enrolled. Patients performed an APA program, 3 sessions/week, for 9 weeks. Exercises focused on balance, walking, strength and functional activities. Functional effects were assessed by Six Minute Walking Test (6MWT), Five Time Sit to Stand Test (FTSST), Berg Balance Scale (BBS), Sit and Reach Test (SRT), and Timed Up and Go test (TUG). Motor impairment and disability were assessed using the Unified Parkinson's Disease Rating Scale - part III (UPDRS-III) and the Hoehn and Yahr Scale, respectively. Non-motor symptoms were evaluated by PD Fatigue Scale (PFS), Beck Depression Inventory II (BDI-II) and PD Quality of life scale, 8 items (PDQ-8). A significant decrease in resting HR (67.55 ± 10.85 vs 70.22 ± 12.34 bpm, p < 0.05) and a significant increase in walked distance (p < 0.0005) were observed. A significant impairment of the muscles strength was noted (FTSST, p < 0.05). BBS showed a significant increase in balance abilities (p < 0.0005) and safety with mobility (TUG, p < 0.005) was enhanced. Finally, a significant improvement in motor and non-motor symptoms was detected: UPDRS-III (p < 0.00005), PFS (p < 0.005), BDI-II (p < 0.05) and PDQ-8 (p < 0.05). A tailored exercise program in PD patients could be effective as an adjunct to conventional therapy on improving daily activities, motor and non-motor symptoms, with better QoL.

Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson's disease

Parkinson's disease (PD) is characterized by progressive loss of nigrostriatal dopaminergic neurons that results in motor deficits including resting tremor, rigidity, bradykinesia, and postural instability. Despite decades of intensive study, the underlying molecular mechanisms are not fully understood. Multiple lines of evidence indicate that mitochondrial dysfunction and oxidative stress contribute to neuronal death, which is the key feature of neurodegeneration. Mitochondria are pivotal organelles that host essential functions in neuronal viability including energy production, oxidative phosphorylation, calcium buffering, redox homeostasis and apoptosis. SIRT5, which localizes in the mitochondrial matrix, is nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. The physiological and pathophysiological functions of SIRT5 in vivo remain elusive although it is known to be an important energy sensor. Here, we investigated the role of SIRT5 in the pathogenesis of PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We present evidence that SIRT5 deficiency, by itself, does not affect motor and non-motor functions; however, lack of SIRT5 exacerbates MPTP-induced motor deficits. Consistently, MPTP-exposed SIRT5 knockout mice exhibited more severe nigrostriatal dopaminergic degeneration than that observed in wild-type controls. Furthermore, deletion of SIRT5 leads to a larger decrease, relative to control, in the expression level of manganese superoxide dismutase (SOD2), a mitochondria-specific antioxidant enzyme, after MPTP induction. These findings indicate that SIRT5 ameliorates MPTP-induced nigrostriatal dopaminergic degeneration via preserving mitochondrial antioxidant capacity.