Low activity of key phospholipid catabolic and anabolic enzymes in human substantia nigra: possible implications for Parkinson's disease

Ross, Brian M.; Moszczynska, Anna; Erlich, Jeffrey C; Kish, Stephen J.

doi:10.1016/s0306-4522(97)00454-5

Cited by 43 publications

(29 citation statements)

References 26 publications

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“…Selective degeneration of dopaminergic neurons in the substantia nigra has been suggested to be related to low activity of phospholipid catabolic/ anabolic enzymes, which may promote the oxidative membrane damage associated with Parkinson's disease that begins at 15-30 years of age ( 315 ). Many recessive loci have been linked to Parkinson's disease; however, they all do not associate with the disease.…”

Section: Ipla 2 ␤ and Diseasesmentioning

confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

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The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

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Section: Ipla 2 ␤ and Diseasesmentioning

confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

View full text Add to dashboard Cite

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“…Furthermore, it has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases and that the substantia nigra region has distinct phospholipid metabolism compared with other brain regions (18). It is interesting to note that the mutation of yeast genes controlling lipid metabolism augments α-synuclein toxicity, a central component of inclusion bodies in PD (19).…”

Section: Park2 Mutations Associate With An Autosomal Recessive Juvenilementioning

confidence: 99%

Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells

Kim¹,

Stevens²,

Akter³

et al. 2011

J. Clin. Invest.

185

162

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It has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases. Consistent with this, emerging epidemiologic evidence links lipid alterations with Parkinson disease (PD), and disruption of lipid metabolism has been found to predispose to α-synuclein toxicity. We therefore investigated whether Parkin, an E3 ubiquitin ligase found to be defective in patients with early onset PD, regulates systemic lipid metabolism. We perturbed lipid levels by exposing Parkin +/+ and Parkin -/-mice to a high-fat and -cholesterol diet (HFD). Parkin -/-mice resisted weight gain, steatohepatitis, and insulin resistance. Introduction PARK2 mutations associate with an autosomal recessive juvenileform of Parkinson disease (PD) (1). However, the role of Parkin in the development of PD in mice is surprisingly modest, as the genetic deletion of Parkin (2, 3) and the combined KO of Parkin with additional "candidate Parkinson susceptibility genes" PINK1 and DJ-1 do not substantially replicate the human condition (4). These unexpected findings suggest that the biological function of Parkin may not primarily modulate neurodegeneration but rather that PARK2 mutations increase biological susceptibility to stressors that manifest with substantia nigra neurodegeneration. Thus, the characterization of the functional actions of Parkin could be instrumental in delineating its role in the pathophysiology underpinning the development of PD.Parkin encodes an E3 ubiquitin protein ligase and contains 465 amino acids with multiple distinct domains, including a ubiquitinlike domain, a unique Parkin-specific domain, 2 RING domains, and an in-between-RING domain (5). The structure of this protein with its multiple binding domains is most likely central to the myriad of functions prescribed to Parkin (6). Additionally, the subcellular location of Parkin appears to be dynamic, with a predominant cytosolic localization with redistribution to the nucleus (7) and to the outer mitochondrial membrane (8, 9). Parkin exhibits mono- and multiubiquitination functions (10), and studies show that classical as well as nonclassical ubiquitin linkages facilitate proteosome-dependent and independent Parkin effects (11)(12)(13)(14).

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“…The most cited neurodegenerative role of Fe is its participation in generation of free radicals in the Fenton reaction [43]. The increased level of Fe in ALS (2) motor neuron can confirm this putative mechanism of cell death.…”

Section: Discussionmentioning

confidence: 85%

Implementation of X-ray Fluorescence Microscopy for Investigation of Elemental Abnormalities in Amyotrophic Lateral Sclerosis

Tomik

Chwiej

Szczerbowska-Boruchowska

et al. 2006

Neurochem Res

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The abnormalities of metallochemical reactions may contribute to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). In the present work, an investigation of the elemental composition of the gray matter, nerve cells and white matter from spinal cord tissues representing three ALS cases and five non-ALS controls was performed. This was done with the use of the synchrotron microbeam X-ray fluorescence technique (micro-SRXRF). The following elements were detected in the tissue sections: P, S, Cl, K, Ca, Fe, Cu, Zn and Br. A higher accumulation of Cl, K, Ca, Zn and Br was observed in the nerve cell bodies than in the surrounding tissue. Contrary to all other elements, Zn accumulation was lower in the white matter areas than in the gray matter ones. The results of quantitative analysis showed that there were no general abnormalities in the elemental accumulation between the ALS and the control group. However, for individual ALS cases such abnormalities were observed for the nerve cells. We also demonstrated differences in the elemental accumulation between the analyzed ALS cases.

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Low activity of key phospholipid catabolic and anabolic enzymes in human substantia nigra: possible implications for Parkinson's disease

Cited by 43 publications

References 26 publications

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells

Implementation of X-ray Fluorescence Microscopy for Investigation of Elemental Abnormalities in Amyotrophic Lateral Sclerosis

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