Upregulation of dopamine D2 receptors in dopaminergic drug-naive patients with Parkin gene mutations.

Medicated patients with Parkinsonism and parkin gene mutations have been reported to show a significant decrease in striatal dopamine D2 receptors (D2R) in comparison to medicated idiopathic Parkinson's disease (IPD) patients with similar age and disease severity. The aim of this study was to verify whether the genetic defect per se is responsible for this decrease. We have studied with [11C]raclopride (RAC) positron emission tomography (PET) in a group of 14 sporadic patients with parkin-linked Parkinsonism, 6 of whom had never received levodopa or dopamine agonists. The remaining 8 patients had been treated with levodopa for at least 5 years. Presynaptic striatal [18F]dopa storage was not significantly different between these two groups of patients. In untreated parkin-positive patients, significant putaminal increases in RAC-binding potential (BP) were found in comparison to an age-matched healthy control group by using a classical region of interest approach and statistical parametric mapping. In contrast, levodopa-treated parkin-positive patients showed significant decreases in RAC-BP in the caudate and putamen when compared to an age-matched healthy control group. The RAC PET findings revealed that striatal D2R upregulation occurs in dopaminergic drug-naive parkin-positive patients, in a similar fashion to the upregulation reported in drug-naive IPD. D2R downregulation observed in medicated parkin-positive patients, therefore, is not caused primarily by the genetic defect itself. Parkin-positive patients appear to have a greater susceptibility to the exposure to dopaminergic medication than IPD patients, which in turn might be an indirect effect of their genetic mutation.     

Diagnostic considerations in juvenile parkinsonism.

Juvenile parkinsonism (JP) describes patients in whom the clinical features of parkinsonism manifest before 21 years of age. Many reported cases that had a good response to levodopa have proved to have autosomal recessive juvenile parkinsonism (AR-JP) due to mutations in the parkin gene. With the exception of parkin mutations and dopa-responsive dystonia, most causes are associated with the presence of additional neurological signs, resulting from additional lesions outside of the basal ganglia. Lewy body pathology has only been reported in one case, suggesting that a juvenile form of idiopathic Parkinson's disease may be extremely rare.     

早发性帕金森病parkin基因的一个新的点突变

目的：观察不同亚型帕金森病（Parkinson's disease,PD）患者中是否存在parkin基因新的突变以及突变的分布，探讨parkin基因在PD发病机理中的可能作用。方法：70例患者被分为早发性PD和晚发性PD，70名正常体检者为对照组。以基因组DNA为模板，扩增parkin基因的全部12个外显子，然后行单链构象多态性（single-strand conformation polymorphism,SSCP）电泳观察，对泳动异常者进行DNA序列测定，以确定外显子中存在的突变及其分布。结果：70例患者中有4例SSCP泳动异常，测序证实1例早发性PD患者的外显子7存在1个未曾报道过的新的点突变位点Gly284Arg。结论：parkin基因点突变也是我国早发性PD患者的致病原因之一。     

Mechanism of neurodegenerative disease: role of the ubiquitin proteasome system

Many neurodegenerative disorders such as Alzheimer's disease (AD) Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are characterized by neuronal damage that may be caused by toxic, abnormal, aggregation‐prone proteins. The purpose of this review is threefold: 1) to provide the reader with an overview of the genes involved in the abnormal processing and accumulation of misfolded proteins in neurodegenerative diseases using PD as a model disease; 2) to understand the cellular mechanisms for disposal of abnormal proteins, and the effects of toxic protein accumulation on ubiquitin proteasome system (UPS) and neuronal survival and 3) to discuss the development and challenges of cell culture and animal models for a rational and effective treatment for these disorders.     

An updated review of Parkinson's disease genetics and clinicopathological correlations

Knowledge regarding the pathophysiological basis of Parkinson's disease (PD) has been greatly expanded over the past two decades, with extraordinary contributions from the field of genetics. However, genetic classifications became complex, difficult to follow, and at times misleading, by placing well‐established monogenic forms of the disease along with others associated with risk loci, often ill characterized. The present paper summarizes the genetic, clinical, and neuropathological findings of the currently described monogenic forms of PD and also approaches the progress made in determining genetic risk factors for PD. Furthermore, the text incorporates the data into a recently proposed classification system that will hopefully bring a “user‐friendly” approach to this issue. This paper also highlights a number of inconsistencies regarding classification of PD as a single, unique clinicopathological entity—in fact, in order to achieve the development of truly innovative therapies, PD should probably be regarded clinically as a “Parkinson's disease cluster”, instead of a single disease. In the future, we hope that an in‐depth and groundbreaking understanding of PD will allow the development of truly disease‐modifying therapies that will target the molecular processes responsible for the cascade of pathological events underlying each form of PD.     

Self‐administration of methamphetamine alters gut biomarkers of toxicity

Methamphetamine (METH) is a highly abused psychostimulant that is associated with an increased risk for developing Parkinson's disease (PD). This enhanced vulnerability likely relates to the toxic effects of METH that overlap with PD pathology, for example, aberrant functioning of α‐synuclein and parkin. In PD, peripheral factors are thought to contribute to central nervous system (CNS) degeneration. For example, α‐synuclein levels in the enteric nervous system (ENS) are elevated, and this precedes the onset of motor symptoms. It remains unclear whether neurons of the ENS, particularly catecholaminergic neurons, exhibit signs of METH‐induced toxicity as seen in the CNS. The aim of this study was to determine whether self‐administered METH altered the levels of α‐synuclein, parkin, tyrosine hydroxylase (TH), and dopamine‐β‐hydroxylase (DβH) in the myenteric plexus of the distal colon ENS. Young adult male Sprague‐Dawley rats self‐administered METH for 3 h per day for 14 days and controls were saline‐yoked. Distal colon tissue was collected at 1, 14, or 56 days after the last operant session. Levels of α‐synuclein were increased, while levels of parkin, TH, and DβH were decreased in the myenteric plexus in the METH‐exposed rats at 1 day following the last operant session and returned to the control levels after 14 or 56 days of forced abstinence. The changes were not confined to neurofilament‐positive neurons. These results suggest that colon biomarkers may provide early indications of METH‐induced neurotoxicity, particularly in young chronic METH users who may be more susceptible to progression to PD later in life.     

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

Mutations or deletions in PARKIN/PARK2, PINK1/PARK6, and DJ-1/PARK7 lead to autosomal recessive parkinsonism. In Drosophila, deletions in parkin and pink1 result in swollen and dysfunctional mitochondria in energy-demanding tissues. The relationship between DJ-1 and mitochondria, however, remains unclear. We now report that Drosophila and mouse mutants in DJ-1 show compromised mitochondrial function with age. Flies deleted for DJ-1 manifest similar defects as pink1 and parkin mutants: male sterility, shortened lifespan, and reduced climbing ability. We further found poorly coupled mitochondria in vitro and reduced ATP levels in fly and mouse DJ-1 mutants. Surprisingly, up-regulation of DJ-1 can ameliorate pink1, but not parkin, mutants in Drosophila; cysteine C104 (analogous to C106 in human) is critical for this rescue, implicating the oxidative functions of DJ-1 in this property. These results suggest that DJ-1 is important for proper mitochondrial function and acts downstream of, or in parallel to, pink1. These findings link DJ-1, pink1, and parkin to mitochondrial integrity and provide the foundation for therapeutics that link bioenergetics and parkinsonism.     

Impairment of the ubiquitin-proteasome system associated with extracellular transthyretin aggregates in familial amyloidotic polyneuropathy

The ubiquitin-proteasome system (UPS) has been associated with neurodegenerative disorders of intracellular protein aggregation. We have studied the UPS in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder caused by extracellular deposition of mutant transthyretin (TTR). The studies were conducted in TTR-synthesizing and non-synthesizing tissues from affected individuals, in transgenic mouse models for FAP, and in neuronal or Schwannoma cell lines cultured with TTR aggregates. In human FAP tissues presenting extracellular TTR aggregates, ubiquitin-protein conjugates were up-regulated, the proteasome levels were decreased and parkin and alpha-synuclein expression were both decreased. A similar response was detected in mouse models for TTR V30M or L55P. On the other hand, the liver, which normally synthesizes variant TTR V30M, did not show this response. Furthermore, transgenic mice immunized to decrease TTR deposition showed a significant reduction in ubiquitin levels and an increase in parkin and alpha-synuclein levels in comparison to control mice. Studies performed in cell lines with aggregates in the medium resulted in increased ubiquitin and decreased parkin levels. The overall results are indicative of TTR deposition as an external stimulus to an intracellular UPS response in FAP.