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Multiple System Atrophy : Mitochondria Dysregulation, Reprogramming and Alternative of Neuroprotective Agents

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12 January 2023

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12 January 2023

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Abstract
A progressive and chronic neurological condition called MSA (Multiple System Atrophy) is characterized clinically by varying degrees of dysautonomia, cerebellar ataxia, and parkinsonism. The concept of mitochondrial dysregulation in MSA is one perspective in handling this neurodegenerative disease. Damage to functional mitochondria is driven by the presence of ɑ-Synuclein-induced mitochondrial localization. The goal of MSA treatment up until now has been to reduce symptoms. One of the innovations in the treatment of MSA could be the novel idea based on mitochondrial reprogramming pathways. Mitochondrial reprogramming can be done in various ways in which the use of hydrogen, magnesium and low-dose hydrogen peroxide.
Keywords: 
Hydrogen
;  
Mitochondrial Dysregulation
;  
MSA
;  
Multiple System Atrophy
Subject: 
Medicine and Pharmacology  -   Neuroscience and Neurology

Introduction

It is well known that multiple system atrophy (MSA) is a neurodegenerative disease experienced by adults. There are several characteristics of this disease, namely dysautonomia and parkinsonism. This MSA disease is pathologically characterized by the aggregation and localization of α-synuclein, rapid disease progress, and lack of response to L-DOPA. α-Synuclein is known to have mitochondria localization, affecting the disharmony of energy supply in MSA patients [1,2,3,4]. The main themes in this article are the concept of MSA with a focus on mitochondrial dysregulation and its relation to mitochondrial reprogramming and research related to MSA therapy to date and future perspectives of MSA treatment.

Mitochondria Dysregulation in MSA

There are two categories of MSA, namely cerebellar and parkinsonian [5,6,7]. In MSA patients who have a cerebellar type, ataxia is found. Ataxia is a neurological condition that impacts the lack of coordination in the movement of the muscles. Changes in the condition of this dysfunction are usually characterized by changes in the ability to speak and eye movements of an abnormal nature. Meanwhile, in MSA patients with a parkinsonian type, there is extrapyramidal motor abnormality. This neurological condition is related to lesions in the basal ganglia. This situation causes the inability of MSA sufferers to initiate changes in movement activities easily and quickly. In addition, parkinsonian-type MSA sufferers also experience muscular rigidity, and this condition is a condition of the body's muscles that contract continuously and eventually limit passive movement. Furthermore, there are also difficulties in maintaining muscle movement in the fingers, feet and other places in the body in a fixed position, commonly referred to as athetosis [8,9,10].
Multiple system atrophy is closely related to α-synuclein, where α-synuclein is a synaptic protein which, in physiological conditions, is an unfolded protein produced by neuronal cells [11,12,13,14,15]. This protein can affect mitochondria, as it is known that mitochondria are crucial cell organelles in the context of energy. The impact of α-synuclein on signalling calcium ions (Ca2+) within the mitochondria can affect the exchange of those ions and the physical interaction between the mitochondria and the ER. Some cases, such as the low expression of A53T caused by the influence α-synuclein with mitochondria, can cause fragmentation of the mitochondria [16,17,18,19].
Localization of α-synuclein in various membranes in mitochondria can be found in MSA patients. MAM (Mitochondria-associated membranes) is a part that has a special function in the relationship between mitochondria and ER (endoplasmic reticulum), where this part functions in the regulation of mitochondrial dynamics and division also unfolded protein response [20,21,22,23]. Localization α-synuclein in this membrane will increase the uptake of Ca2+ if it is in an overexpression state. At the same time, it will change mitochondrial morphology if it is in a downregulation condition [16]. α-Synuclein residing in MAM demonstrated interacting with ER VAPB (Vesicle-associated membrane protein-associated protein B) [24,25].
α-Synuclein is also located in other parts of the mitochondria, such as OMM (Outer Mitochondrial Membrane), IMS (Inter-membrane Space), IMM (Inner Mitochondrial Membrane), and MM (Mitochondrial Matrix). In the OMM section of this protein, it is known that α-synuclein can bind to lipids and membranes [26]. Localization of this protein is also found in dopaminergic neurons [27]. The data show that binding α-synuclein to OMM causes mitochondrial fragmentation of both DRP1-independent and MFN [28]. The amount of this protein that binds to OMM is known to affect mitochondrial size in both wild and A53T types of α-synuclein [19].
Another part of the mitochondria that is the localization site of α-synuclein is the IMS (Inter-membrane Space). The interactions in this section can lead to increased ROS production and potential alteration of mitochondrial membranes. Basal conditions are also one of the conditions for α-synuclein translocation in IMS [28,29]. Whereas in IMM (Inner Mitochondrial Membrane), it is known that α-synuclein can bind to IMM through N-terminus [30]. Then in MM (Mitochondrial Matrix) α-synuclein can bind to γ, B and D chains of ATP synthase. Aggregation conditions and mutations of α-synuclein cause loss of mitochondria function and accelerate the process of damage to neurodegenerative disease [31,32,33,34]. In general, translocation of α-synuclein in mitochondria is mediated by lipid binding, VDAC proteins and TIM/TOM complexes [35,36]. The compilation of the results of these studies is represented in Figure 1.

Mitochondrial Reprogramming

In relation to mitochondria that are damaged in various neurodegenerative diseases, it is necessary to know that several studies target mitochondrial reprogramming. Research on mitochondrial reprogramming in MSA is minimal. However, in types of diseases such as Parkinson's disease (PD), mitochondrial impairment and research have been carried out related to mitochondrial and metabolic reprogramming. It is known that there is a mutation of the PINK1 gene in PD patients. This gene functions in the encoding of the mitochondrial kinase [37,38,39,40]. The research of Tufi et al. (2014) showed that genetic and pharmacological manipulation of nucleotide metabolism pathways could be a solution to improve mitochondrial function. Mitochondria reprogramming through the administration of folic acid and dNS (deoxyribonucleosides) through the mechanism of mitochondrial biogenesis [41]. In addition, several studies on glucose metabolic dysfunction related to neurodegenerative diseases can also use the concept of metabolic reprogramming. It should be noted that the oxidation of glucose to CO2 to produce ATP through the oxidative phosphorylation pathway occurs in the mitochondria. Mitochondria are the main actors in cellular energy supply, affecting amino acid synthesis and directly affecting the production of neurotransmitters and protein synthesis (Table 1). Mitochondrial changes in neurodegenerative disease affect neuronal function [42,43].
Metabolic reprogramming in neurodegenerative disease can be done in various ways, namely hypoxia and exercise-induced. IHHT (intermittent hypoxia-hyperoxia training) is used in patients aged with MCI (mild cognitive impairment) conditions, which is a precursor to Alzheimer's disease. Training in using IHHT improves cognitive function in patients significantly, and it is known that decreased expression of Amyloids-β after administration of IHHT indicates a neuroprotective mechanism. Similarly, intermittent hypoxic conditioning can improve short-term memory in patients with MCI [81,82,83]. While reprogramming using exercise-induced affects several points, namely an increase in temperature and blood pressure, hypoxia conditions and the impact on mitochondrial skeletal muscles, biogenesis, fusion and respiration of mitochondrial. In addition to the mitochondria in the skeletal muscle, there are several theories regarding direct neuroprotective signalling. As it is known that mitochondria not only react to signaling molecules but can be transferred between cells. Several studies have shown that systemic administration of mitochondria into the blood results in the relocation of mitochondria to brain regions and benefits mouse models of Parkinson's and Alzheimer's disease [84,85,86,87]. The possibility of using the concept in handling MSA in the future is not impossible.

Management of MSA

The treatment of MSA to date has focused on symptom management that occurs in each patient, which is very specific. This condition can occur because MSA is a multisystem disease. So various fields of science such as cardiology, neurology, urology, psychiatry, pulmonary, and dietary are needed to create a comprehensive system for handling this disease. Some MSA symptoms, namely parkinsonism, can be given Armatandine 100 mg x 3 times daily or levodopa / Carbidopa drugs (200-300 mg x 3-4 times daily) and followed by physical therapy and exercise [88,89,90,91,92,93]. Then, for spasticity symptoms, muscle relaxants such as tizanidine or baclofen can be used, while symptom dystonia can use trihexyphenidyl [94,95,96,97]. As it is known that symptom ataxia also occurs in MSA patients and although no medications have been able to improve this symptom significantly, intensive physical therapy can help the patient's condition [98,99,100,101,102]. As for sleep disorders such as REM sleep behavior disorder or restless legs syndrome, MSA patients can be given clonazepam 0.5 to 2 mg at night, but if an apnea condition follows the symptoms, it is more advisable to give melatonin with an initial dose of 3 mg. During apnea, changes in sleeping position, neurostimulation and weight loss can be made [103,104,105,106,107]. Table 2 summarizes some therapies that have been and are being carried out for MSA disease.

Alternative neuroprotective agents in MSA

Molecular Hydrogen (H2)

Several recent studies have shown that molecular hydrogen has therapeutic capabilities in various human diseases such as metabolic syndrome, ischemia-reperfusion injury, organ transplantation, type 2 diabetes mellitus and other neurodegenerative diseases [118,119,120,121,122,123,124,125,126]. The advantage of using hydrogen is that it can be applied in various ways, namely through gas therapy, in the form of drinks as hydrogen-water or dialysis or intravenous injection (IV). The use of IV has the advantage that it can bring hydrogen molecules directly into the bloodstream. Matsumoto et al. (2013) examined the use of oral hydrogen water for PD disease, where neuroprotective effects were found through mediation using ghrelin production [127]. The concentration of H2 that can show a protective effect on dopamine neurons is 0.04-0.8 mM. Table 3 is a compilation of the neuroprotective effects of molecular H2 through various mechanisms in neurodegenerative diseases.

Magnesium

Magnesium is a macro element that is very important for humans, especially its function, which is involved in neurotransmission and body metabolism. Some studies show that magnesium deficiency can cause neurological disorders especially synaptic plasticity [151,152,153]. In Parkinson's disease, the role of magnesium is seen in inhibiting the aggregation of α-synuclein [154]. The function of magnesium itself is most widely studied for cerebral ischemic disease [155]. Magnesium, in physiological conditions, can regulate neuronal activity [156]. Associated with mitochondrial magnesium reprogramming can maintain mitochondrial function and energy metabolism of cells [157]. Table 4 is a compilation of several studies using magnesium as a supplement in treating cerebral ischemic disease. It is possible that the use of magnesium supplements can improve the condition of people with other neurodegenerative diseases, including MSA. More research is needed regarding this hypothesis.

Low Concentration of Hydrogen Peroxide

H2O2 molecules are frequently regarded as poisonous molecules that have a harmful impact on numerous levels of life, both cellular and tissue [165,166]. Many studies, however, have discovered that the concentration of this molecule impacts the function of the molecules in the body. Low H2O2 concentrations can bring a variety of benefits. This molecule will be broken down into H2O and ½ O2 with the help of the enzyme catalase (CAT). The breakdown product, particularly O2, has the potential to become an alternate supply in the body and reduce the generation of reactive oxidant species. Several studies have revealed that the H2O2 molecule has a variety of beneficial roles, including as a regulatory signal in metabolism [167,168,169,170,171,172]. H2O2 has a neuroprotective effect and can prevent the progression of apoptosis in PC12 cell lines at low concentrations of 10 M. This indicates that utilizing molecules at low concentrations improves mitochondrial activity [173].

Conclusion and Future Directions

This review journal has systematically discussed MSA, both characteristics and mitochondria impairment caused by α-synuclein, as well as the possibility of mitochondria reprogramming through the administration of several alternative neuroprotective agents such as hydrogen, magnesium and low-dose hydrogen peroxide. The management of MSA to date has also been described, and it needs to be highlighted that the handling condition is still in the form of managing symptoms. Future research needs to be carried out in preclinic and clinical trials to prove MSA management using some of the alternative neuroprotective agents above, both in single and complex forms, then for the initial stage an in-silico study can be carried out. The use of protein modeling, docking and molecular dynamic simulation can be maximized [174,175,176,177].

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Preprints 67327 g001
Figure 1. Localization of α-synuclein in mitochondrial membranes.
Figure 1. Localization of α-synuclein in mitochondrial membranes.
Preprints 67327 g001
Table 1. The connection between metabolic disorders and neurodegenerative disease.
Table 1. The connection between metabolic disorders and neurodegenerative disease.
Neurodegenerative Diseases Neuronal Glucose and Glucose metabolism (Decrease Uptake) Dysfunctional in Mitochondria Ref
Alzheimer’s Disease ↓ Expression of glucose transporter Imbalance in mitochondrial fission and fusion [44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]
↑ Metabolism of ketone body ↓ Axonal transport
↓ Metabolic complex activity ↓ Mitochondria in a cell
↑ Aerobic Glycolysis
↑ Pyruvate dehydrogenase in inactive form
Parkinson’s Disease ↓ NADH dehydrogenase Mutations in Leucine-rich repeat kinase (LRRK2) [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80]
↓ 6-phosphogluconate dehydrogenase Mutations in PTEN induced kinase 1 (PINK1)
↓ G6P dehydrogenase Mutations in Htr A serine peptide 2 (HTRA2)
Table 2. Therapeutic Drugs for Multiple System Atrophy.
Table 2. Therapeutic Drugs for Multiple System Atrophy.
Mechanism Therapeutic drug Results Ref
Neuroprotection Riluzole No effect on progression of MSA (Phase III) [108]
Mitochondrial Function CoQ10 Ongoing (Phase II) [109]
Neuroprotection Mesenchymal stem cells Delayed progression of MSA (Phase II) [110]
α-Synuclein
(Inhibition of aggregation process)		 Lithium Drug trial is terminated (severe side effect such as death, daytime sleepiness and tremor) [111]
α-Synuclein (Modulates of oligomerization process) Anle138b Ongoing (Phase I) [112]
α-Synuclein
(Inhibition of aggregation process)		 Anti-miR-101 Decreased GCIs and increased autophagy (Pre-clinic) [113]
Neuroprotection Exendin-4 Decreased α-synuclein oligomers, cell death and insulin resistance (Phase II) [114]
α-Synuclein
(Inhibition of aggregation process)		 CLR01 Decreased synuclein oligomers, GCIs, microglial activation and motor impairment (Pre-clinic) [115]
Belnacasan (VX-765) Decreased synuclein oligomers, GCIs, microglial activation (Pre-clinic) [116]
Rifampicin No offect on progression of MSA (Phase II) [117]
Table 3. Neuroprotective Effects of Molecular Hydrogen.
Table 3. Neuroprotective Effects of Molecular Hydrogen.
Hydrogen administration Neurodegenerative Disease Mechanism of Neuroprotective Effects Ref
Oral and inhalation Parkinson’s disease Activation of gastric ghrelin system, minimizing the loss of dopaminergic cells, and reducing oxidative stress [127,128,129,130,131,132,133]
Oral, inhalation, intravenous and intraperitoneal injection Ischemia Stabilization of mitochondrial function, blood-brain barrier maintenance, reduction of endoplasmic reticulum stress, oxidative and inflammatory stress [134,135,136,137]
Intraperitoneal injection Subarachnoid hemorrhage Anti apoptosis and inhibiton of oxidative stress [138,139]
Oral, intracerebral and intraperitoneal injection Alzheimer’s disease Up regulation of Sirt1-FoxO3a axis, stimulating AMPK, inhibiting the activation of NLRP3 and JNK [140,141,142,143,144,145]
Intraperitoneal injection and inhalation Brain injury Blood-brain barrier maintenance and stabilization of mitochondrial function [146,147,148,149,150]
Table 4. Magnesium Function in Cerebral Ischemic Disease.
Table 4. Magnesium Function in Cerebral Ischemic Disease.
Magnesium Administration Magnesium Type and Dose Results Ref
Intravenous injection MgSO4 (360 μmol/kg) Reduction of infarct volume if combined with mild hypothermia [158]
Intraperitoneal injection MgCl2 (1 mmol/kg) Reduction of infarct volume [159]
Inraarterial injection MgSO4 (90 mg/kg) Reduction of infarct volume [160]
Intraperitoneal injection MgSO4 (2 g/kg) Reduction of neuronal apoptosis [161]
Inraarterial injection MgSO4 (750 μmol/kg) Reduction of infarct volume [162]
Intravenous injection MgSO4 (90 mg/kg) Reduction of infarct volume [163]
Intraperitoneal injection MgSO4 (250 mg/kg) Reduction of infarct volume [164]
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