iPLA2β Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology

Blanchard, H.; Taha, Ameer Y.; Cheon, Yewon; Kim, Hyung‐Wook; Turk, John; Rapoport, Stanley I.

doi:10.1007/s11064-014-1342-y

Cited by 23 publications

(18 citation statements)

References 60 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on our findings, rupture of the presynaptic membrane might secondarily activate glial cells. Biochemical analysis of PLA2G6 KO mice did not reveal decreased expression levels of molecules associated with presynaptic function, such as α‐synuclein and dopamine active reuptake transporter . This indicates that a subset of well‐functioning presynapses (Figs b1, a) could compensate for dysfunctional and degenerated presynapses (Figs b2,b3, b).…”

Section: Swelling Of the Presynaptic Membrane And Axon Terminal Degenmentioning

confidence: 94%

See 1 more Smart Citation

Neuroaxonal dystrophy in PLA2G6 knockout mice

et al. 2015

View full text Add to dashboard Cite

The PLA2G6 gene encodes group VIA calciumindependent phospholipase A2 (iPLA2β), which belongs to the PLA2 superfamily that hydrolyses the sn-2 ester bond in phospholipids. In the nervous system, iPLA2β is essential for remodeling membrane phospholipids in axons and synapses. Mutated PLA2G6 causes PLA2G6-associated neurodegeneration (PLAN) including infantile neuroaxonal dystrophy (INAD) and adult-onset dystoniaparkinsonism (PARK14), which have unique clinical phenotypes. In the PLA2G6 knockout (KO) mouse, which is an excellent PLAN model, specific membrane degeneration takes place in neurons and their axons, and this is followed by axonal spheroid formation. These pathological findings are similar to those in PLAN. This review details the evidence that membrane degeneration of mitochondria and axon terminals is a precursor to spheroid formation in this disease model. From a young age before the onset, many mitochondria with damaged inner membranes appear in PLA2G6 KO mouse neurons. These injured mitochondria move anterogradely within the axons, increasing in the distal axons. As membrane degeneration progresses, the collapse of the double membrane of mitochondria accompanies axonal injury near impaired mitochondria. At the axon terminals, the membranes of the presynapses expand irregularly from a young age. Over time, the presynaptic membrane ruptures, causing axon terminal degeneration. Although these processes occur in different degenerating membranes, both contain tubulovesicular structures, which are a specific ultrastructural marker of INAD.This indicates that two unique types of membrane degeneration underlie PLAN pathology. We have shown a new pathological mechanism whereby axons degenerate due to defective maintenance and rupture of both the inner mitochondrial and presynaptic membranes. This degeneration mechanism could possibly clarify the pathologies of PLAN, Parkinson disease and neurodegeneration with iron accumulation (NBIA), which are assumed to be due to the primary degeneration of axons.Key words: calcium independent phospholipaseA2β (iPLA2β), infantile neuroaxonal dystrophy (INAD), membrane, mitochondria, PLA2G6.

show abstract

Section: Swelling Of the Presynaptic Membrane And Axon Terminal Degenmentioning

confidence: 94%

“…9d). Glial cells including astrocytes and microglia are activated in the brain 35 and cerebellum. 28 Based on our findings, rupture of the presynaptic membrane might secondarily activate glial cells.…”

Section: Swelling Of the Presynaptic Membrane And Axon Terminal Degenmentioning

confidence: 99%

Neuroaxonal dystrophy in PLA2G6 knockout mice

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Additional evidence of iPLA 2 ␤ involvement in neurodegenerative disorder include: association of a subset of Shindler's disease in infants with PLA2G6 mutations ( 348 ); elevations in iPLA 2 ␤ in patients with bipolar l disorder and a history of psychosis ( 349 ); neuro-infl ammation and associated neuropathology with motor dysfunction in later life due to iPLA 2 ␤ -defi ciency ( 350 ); and roles for iPLA 2 ␤ during early benefi cial stages of myelin breakdown following peripheral nerve injury ( 351 ) and detrimental demyelination due to spinal cord injury ( 352 ), brain endothelial cell migration and proliferation ( 353 ), antidepressant-like effects of maprotiline ( 354 ), and pro-oxidative signaling related to ethanol-induced neurotoxicity ( 355 ).…”

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

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

show abstract

“…It has therefore been postulated that dietary n-3 PUFA supplementation (e.g., as cod liver oil) should be considered in neurologic disorders including PLAN. [73][74][75][76]…”

Section: Vitamin B 5 (Pantothenate) and B 5 Derivatives For Pantothenmentioning

confidence: 99%

Update in Neurodegeneration with Brain Iron Accumulation: Advances in Molecular Diagnosis and Treatment Strategies

Csányi

Papandreou

Cuka³

et al. 2015

J Pediatr Neurol

View full text Add to dashboard Cite

Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term used to clinically describe a group of neurologic conditions associated with high brain iron. To date, there are 10 genetic subtypes described, which share several common clinical features. Novel technologies such as improved magnetic resonance imaging techniques and whole exome sequencing have provided new clinical and genetic insight into these disorders, thereby improving clinical diagnosis for patients. Indeed, precise diagnosis is now possible for approximately 60% of patients with NBIA. Despite these genetic advances, little is known about the exact underlying disease pathways governing many forms of NBIA. In fact, for most subtypes, the causative genes and affected proteins are not directly related to iron homeostasis. Management for all subtypes remains mainly supportive and based on a multidisciplinary approach, but there are promising advances in the development of novel therapeutic strategies. Focusing mainly on the newly described NBIA subtypes, we summarize the clinical phenotypes, genetic basis, and postulated pathophysiological disease mechanisms, and propose an NBIA diagnostic pathway to guide clinical testing and genetic councelling.

show abstract

iPLA2β Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology

Cited by 23 publications

References 60 publications

Neuroaxonal dystrophy in PLA2G6 knockout mice

Neuroaxonal dystrophy in PLA2G6 knockout mice

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

Update in Neurodegeneration with Brain Iron Accumulation: Advances in Molecular Diagnosis and Treatment Strategies

Contact Info

Product

Resources

About