Paraptosis is a form of programmed cell death characterized by cytoplasmic vacuolization, mitochondrial swelling, and endoplasmic reticulum dilation, without the classic features of apoptosis such as caspase activation or DNA fragmentation[1]. This non-apoptotic cell death pathway has emerged as a significant contributor to neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders[2].
The term paraptosis (from Greek para- meaning beside or alongside) was first described in 2000 by Sperandio et al. to distinguish it from apoptosis and necrosis[3]. Unlike apoptosis, paraptosis is characterized by:
Paraptosis involves several distinct molecular pathways:
MAPK Pathway: The MAPK (mitogen-activated protein kinase) signaling cascade, particularly JNK/SAPK and p38, plays a crucial role in paraptotic cell death[4]. These kinases are activated by cellular stress and contribute to mitochondrial dysfunction.
IGF-IR Signaling: Insulin-like growth factor I receptor (IGF-IR) signaling has been shown to regulate paraptosis through the MAPK pathway[5]. Downregulation of IGF-IR can induce paraptotic cell death.
ATP Decline: Progressive ATP depletion characterizes paraptosis, distinguishing it from apoptosis where ATP is required for the execution of cell death[6].
Electron microscopy reveals distinctive features of paraptosis[7]:
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Accumulating evidence suggests that amyloid-beta (Aβ) oligomers can induce paraptotic cell death in neurons[8]. Aβ-mediated paraptosis involves:
The relationship between tau pathology and paraptosis is complex. Hyperphosphorylated tau can:
Alpha-synuclein aggregation, the hallmark of PD, can induce paraptotic cell death in dopaminergic neurons[14]. Mechanisms include:
Mutations in LRRK2 (leucine-rich repeat kinase 2), a common genetic cause of PD, have been linked to paraptotic pathways[18]. LRRK2 G2019S mutation enhances:
Understanding paraptosis opens new therapeutic avenues[19]:
Mitochondrial Protection:
ER Stress Modulation:
Calcium Homeostasis:
Combination Therapies:
Diagnosing paraptosis in human brain tissue remains challenging[20]:
Potential biomarkers for paraptosis include:
Paraptosis represents an important non-apoptotic cell death pathway in neurodegeneration. Unlike apoptosis, which is traditionally considered the primary cell death mechanism in AD and PD, paraptosis may account for a significant portion of neuronal loss that is not responsive to anti-apoptotic therapies. Targeting paraptotic pathways offers novel therapeutic strategies for neurodegenerative diseases.
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D'Amico AG, Maugeri G, Rasà DM, et al. 'Paraptosis: A Non-Apoptotic Cell Death in Neurodegenerative Diseases'. Frontiers in Cellular Neuroscience. 2022. ↩︎
Sperandio S, Poksay K, de Belle I, et al. 'Paraptosis: mediation by MAP kinases and inhibition by Akt/PI3K'. Cell Death & Differentiation. 2004. ↩︎
Kim H, Kim Y, Gwak J, et al. JNK signaling pathway mediates paraptosis in neuronal cells. Journal of Cellular Biochemistry. 2018. ↩︎
Trapani M, D'Amico AG, Maugeri G, et al. 'IGF-IR mediated paraptosis: A new pathway for neurodegenerative diseases'. Journal of Cellular Physiology. 2019. ↩︎
Fontella FU, Gabilan NH, Araujo MS, et al. ATP decline is a hallmark of paraptosis. Neurochemical Research. 2015. ↩︎
Bury M, Gawron B, Włodarczyk A, et al. Ultrastructural characterization of paraptotic cell death. Cell Death & Disease. 2020. ↩︎
Song S, Jing Y, Liu J, et al. Amyloid-beta oligomers induce paraptotic cell death in neurons. Neuroscience Letters. 2019. ↩︎
Rhein V, Song G, Yao X, et al. Amyloid-beta and mitochondria interact in Alzheimer's disease. Journal of Alzheimer's Disease. 2020. ↩︎
Demuro A, Mina E, Kayed R, et al. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. Journal of Biological Chemistry. 2005. ↩︎
Katayama T, Imaizumi K, Manabe T, et al. Induction of neuronal death by ER stress in Alzheimer's disease. Journal of Chemical Neuroanatomy. 2004. ↩︎
Butterfield DA, Drake J, Pocernich C, et al. [ 'Evidence of oxidative damage in Alzheimer''s disease brain: Central role of amyloid beta-peptide'](https://doi.org/10.1016/S1471-4914(01). Trends in Molecular Medicine. 2001. ↩︎
Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nature Reviews Neuroscience. 2007. ↩︎
Xu J, Kao SY, Lee FJ, et al. 'Dopamine-dependent neurotoxicity of alpha-synuclein: A mechanism for selective neurodegeneration in Parkinson disease'. Journal of Biological Chemistry. 2002. ↩︎
Martin LJ, Semenkow S, Hanaford A, et al. Mitochondrial permeability transition pore regulates Parkinson's disease development in mutant alpha-synuclein transgenic mice. Cell Calcium. 2014. ↩︎
Gorbatyuk MS, Gorbatyuk OS. ER stress and unfolded protein response in alpha-synucleinopathies. Experimental Neurology. 2012. ↩︎
Danzer KM, Haasen D, Karow AR, et al. Different species of alpha-synuclein oligomers induce calcium influx and seeding. Journal of Neuroscience. 2007. ↩︎
Lee BD, Dawson VL, Dawson TM. LRRK2 pathways in Parkinson's disease. Molecular and Cellular Neuroscience. 2013. ↩︎
Galluzzi L, Bravo-San Pedro JM, Blomgren K, et al. Cell death-based interventions in neurology. Cell Death & Disease. 2022. ↩︎
Yamada T, Iwasaki Y, Nagashima K, et al. Electron microscopy in neurodegenerative disease diagnostics. Brain Pathology. 2019. ↩︎