Current Understanding of the Molecular Mechanisms in Parkinson's Disease: Targets for Potential Treatments Panchanan Maiti1,2,3,4,5*, Jayeeta Manna6 and Gary L
Total Page：16
File Type：pdf, Size：1020Kb
Maiti et al. Translational Neurodegeneration (2017) 6:28 DOI 10.1186/s40035-017-0099-z REVIEW Open Access Current understanding of the molecular mechanisms in Parkinson's disease: Targets for potential treatments Panchanan Maiti1,2,3,4,5*, Jayeeta Manna6 and Gary L. Dunbar1,2,3,4* Abstract Gradual degeneration and loss of dopaminergic neurons in the substantia nigra, pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease (PD). In addition, half of the PD patients also exhibit frontostriatal-mediated executive dysfunction, including deficits in attention, short-term working memory, speed of mental processing, and impulsivity. The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients. Because, these therapies neither restore the lost or degenerated dopaminergic neurons, nor prevent or delay the disease progression, the need for more effective therapeutics is critical. In this review, we provide a comprehensive overview of the current understanding of the molecular signaling pathways involved in PD, particularly within the context of how genetic and environmental factors contribute to the initiation and progression of this disease. The involvement of molecular chaperones, autophagy-lysosomal pathways, and proteasome systems in PD are also highlighted. In addition, emerging therapies, including pharmacological manipulations, surgical procedures, stem cell transplantation, gene therapy, as well as complementary, supportive and rehabilitation therapies to prevent or delay the progression of this complex disease are reviewed. Keywords: Parkinson’s disease, Neurodegeneration, Protein misfolding, Molecular chaperones, Cell therapy Background Although the exact mechanism of dopaminergic neur- Parkinson disease (PD) is second to Alzheimer’s disease onal loss in SNpc is not well understood. Mitochondrial as the most common age-related complex, idiopathic damage, energy failure, oxidative stress, excitotoxicity, neurological disorder [1]. It is characterized by tremor, protein misfolding and their aggregation, impairment of bradykinesia and muscle rigidity along with impaired protein clearance pathways, cell-autonomous mecha- gait, and posture [2–4]. In addition, about half of the PD nisms and “prion-like protein infection” may be involved patients also exhibit frontostriatal-mediated executive in the onset and progression of PD [3, 8, 9]. Among dysfunction, including deficits in attention, speed of them, protein misfolding and its subsequent accumula- mental processing, verbal disturbances, impairment of tion in intracellular spaces has become a leading hypoth- working memory and impulsivity [5]. Dopaminergic esis for PD [10, 11]. The major misfolded amyloid neuronal loss in the substantia nigra pars compacta protein inclusion observed in the intracellular spaces of (SNpc), and depletion of dopamine (DA) levels in the SNpc neurons in PD is the Lewy bodies (LB) [3, 11, 12], striatum represent the hallmark pathology of PD [6]. which contain several misfolded amyloid proteins, including Experimental evidence indicates that the prefrontal cor- alpha-synuclein (SNCA), phosphorylated tau (p-tau), and tex (PFC), anterior cingulate gyrus, and/or frontostriatal amyloid beta protein (Aβ) [11, 13]. Several environmental pathways are also affected by PD [7]. toxins are associated with sporadic PD (SPD), which can be partially mimicked in experimental animal models of PD, * Correspondence: [email protected]; [email protected] such as the use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri- 1Field Neurosciences Institute Laboratory for Restorative Neurology, Mt. dine (MPTP) and paraquat [14, 15]. Unlike SPD, familial Pleasant, MI 48859, USA cases are rare, and do not follow the prescribed symptoms Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Maiti et al. Translational Neurodegeneration (2017) 6:28 Page 2 of 35 of PD, which makes it more difficult to understand the developed countries [14], due to an increase in the pathogenesis of PD [10, 16]. aged population [14, 27]. Aging is the most dominant Although several new treatments for PD have been risk factor for PD. As such, the cases of PD are very developed [17], none of them effectively halt the pro- low in people under 40 and becomes more prevalent gression of PD. The few symptomatic treatments cur- in individuals in their 70s and 80s [10]. People with rently available, are appropriate for only a limited one or more close relatives who have PD have an in- number of patients. Moreover, side-effects, short-life creased risk of developing the disease themselves, but span, and permeability issues are the major problems the total risk is still just 2–5%, unless the family has for use of these drugs against PD. Interestingly, recent a known gene mutation for the disease [26]. Other developments in stem cell transplantation [18–20] risk factors exist, including exposure to environmental and gene therapies [21, 22] have drawn special atten- toxins [14, 27]. However, most scientists agree that tion as alternative strategies for treating PD. For ex- PD is not, by itself, a fatal disease, but rather, it ample, genetically engineered DA-neurons have shown causes a worsening of normal functioning with time. promising results in mouse models of PD [20, 23]. Interestingly, the average life expectancy of a PD pa- Similarly, using lentiviral or recombinant adeno- tient is generally the same as for normal people [28]. associated viral vectors (rAAV), scientists are able to correct some of the dysfunctional metabolic pathways involved in PD [24]. Further, a very recent develop- Symptoms of PD ment of the gene editing technique, clustered The progression of symptoms in PD may take 15 to regularly-interspaced short palindromic repeats- 20 years or more, but may vary person-to-person [8]. associated protein 9 (CRISPR-Cas9), may prove useful The major symptoms observed in PD patients are cate- for treating PD [22]. Given the pressing need for the gorized into: (i) early symptoms; (ii) primary motor development of new, rational therapies for PD, the symptoms, (iii) secondary motor symptoms, (iv) primary focus of this review is to provide basic conceptual in- non-motor symptoms, and (v) secondary non-motor formation on the molecular mechanisms underlying symptoms (Fig. 1). PD, which may assist in the design of more effective drugs or other treatment strategies. Early symptoms Global scenario and risk factors for PD The early symptoms are subtle and progress slowly, Although the symptoms and therapies for PD were making them difficult to detect. They include mild first mentioned in the “Indian Ayurveda” (5000 BC) tremors, posture difficulty, soft speech, slow handwrit- and Chinese medical text, “Nei-Jing” (500 BC), it was ing, lack of limb movement, abnormal facial expression, James Parkinson, a British physician for whom the loss of focus in thought and speed, fatigue, irritability or disease is named accurately described it as “the depression, without provocation or cause [2, 29]. Some- shaking palsy” in 1817. Epidemiological studies have times the person may be stiff, unsteady, or unusually revealed that PD is world-wide and affects 1–2% of slow, and as the disease progress, the shaking or tremor those older than 65 years, and 4–5% of those aged may appear, which start from one side of the body, they over 85 years [8, 25]. In US, more than one million eventually spread bilaterally over time [2, 29]. Generally, cases have been reported [26]. PD is more common family members or close friends, or daily caretakers are in men (about 1.5 times) than in women [8], and a more likely to detect the emergence of early symptoms higher incidence of PD has been reported in in patients. Fig. 1 Different symptoms of PD. The PD symptoms are categorized into five major subtypes: early, primary motor, secondary motor, primary and secondary non-motor symptoms Maiti et al. Translational Neurodegeneration (2017) 6:28 Page 3 of 35 Primary motor symptoms (ii) Muscle cramps and dystonia. A variety of pain, aches, muscle spasms or dystonia have been (i) Resting Tremor. Shaking of hands, arms, legs, jaw, observed in PD [33]. These muscle cramps can be head, tongue, lips, chin are the primary motor sustained for prolonged periods and can be very symptoms observed in PD (Fig. 1). About 70% of painful. Muscular rigidity is the principal reason for people with PD experience “resting tremor” in the this, which may be exacerbated due to the side- early stage of the disease, either in the hand or foot effects of certain medications [34]. on one side of the body, or less commonly, in the (iii)Sexual dysfunction. Sexual dysfunction is one of the jaw or face [26, 30]. As the disease progresses, both major reasons for deterioration of quality of life of a arms may become affected [26, 30]. Typically, the PD patient. Hyper-sexuality, erectile dysfunction, tremor takes the form of a rhythmic, back-and-forth and difficulties in ejaculation are found in some PD motion at a rate of 4–6 Hz. male patients. Whereas the loss of lubrication and (ii) Rigidity. The rigidity or increase in stiffness or involuntary urination during sex are common in tonicity of a muscle is the second most common female PD patients [35]. The tremor, bradykinesia, symptoms noted in PD patient [31]. The person with muscular rigidity, dyskinesia, hyper-salivation, and PD often feels stiff or weak, pain and cramping in sweating may be the reasons for sexual dysfunction muscles and joints.