The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy

Celine Deneubourg,Mauricio Ramm,Luke J Smith,Olga Baron,Kritarth Singh,Susan C Byrne,Michael R Duchen,Mathias Gautel,Eeva-Liisa Eskelinen,Manolis Fanto,Heinz Jungbluth

doi:10.1080/15548627.2021.1943177

Abstract

ABSTRACT Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable “clinical signature,” including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases. Abbreviations: AC: anterior commissure; AD: Alzheimer disease; ALR: autophagic lysosomal reformation; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ASD: autism spectrum disorder; ATG: autophagy related; BIN1: bridging integrator 1; BPAN: beta-propeller protein associated neurodegeneration; CC: corpus callosum; CHMP2B: charged multivesicular body protein 2B; CHS: Chediak-Higashi syndrome; CMA: chaperone-mediated autophagy; CMT: Charcot-Marie-Tooth disease; CNM: centronuclear myopathy; CNS: central nervous system; DNM2: dynamin 2; DPR: dipeptide repeat protein; DVL3: disheveled segment polarity protein 3; EPG5: ectopic P-granules autophagy protein 5 homolog; ER: endoplasmic reticulum; ESCRT: homotypic fusion and protein sorting complex; FIG4: FIG4 phosphoinositide 5-phosphatase; FTD: frontotemporal dementia; GBA: glucocerebrosidase; GD: Gaucher disease; GRN: progranulin; GSD: glycogen storage disorder; HC: hippocampal commissure; HD: Huntington disease; HOPS: homotypic fusion and protein sorting complex; HSPP: hereditary spastic paraparesis; LAMP2A: lysosomal associated membrane protein 2A; MEAX: X-linked myopathy with excessive autophagy; mHTT: mutant huntingtin; MSS: Marinesco-Sjoegren syndrome; MTM1: myotubularin 1; MTOR: mechanistic target of rapamycin kinase; NBIA: neurodegeneration with brain iron accumulation; NCL: neuronal ceroid lipofuscinosis; NPC1: Niemann-Pick disease type 1; PD: Parkinson disease; PtdIns3P: phosphatidylinositol-3-phosphate; RAB3GAP1: RAB3 GTPase activating protein catalytic subunit 1; RAB3GAP2: RAB3 GTPase activating non-catalytic protein subunit 2; RB1: RB1-inducible coiled-coil protein 1; RHEB: ras homolog, mTORC1 binding; SCAR20: SNX14-related ataxia; SENDA: static encephalopathy of childhood with neurodegeneration in adulthood; SNX14: sorting nexin 14; SPG11: SPG11 vesicle trafficking associated, spatacsin; SQSTM1: sequestosome 1; TBC1D20: TBC1 domain family member 20; TECPR2: tectonin beta-propeller repeat containing 2; TSC1: TSC complex subunit 1; TSC2: TSC complex subunit 2; UBQLN2: ubiquilin 2; VCP: valosin-containing protein; VMA21: vacuolar ATPase assembly factor VMA21; WDFY3/ALFY: WD repeat and FYVE domain containing protein 3; WDR45: WD repeat domain 45; WDR47: WD repeat domain 47; WMS: Warburg Micro syndrome; XLMTM: X-linked myotubular myopathy; ZFYVE26: zinc finger FYVE-type containing 26

Highlights

Genetic defects affecting cellular pathways with fundamental biological functions are often associated with extensive and not infrequently lethal human multisystem disorders. These conditions are often named after the organelle/mechanisms involved and/or the most striking pathological abnormality seen on microscopy, and include ciliopathies, congenital dis orders of glycosylation, cellular trafficking, mitochondrial, as well as glycogen and lysosomal storage disorders
Some of the individual condi tions included within the group of congenital disorders of autophagy may be exceedingly rare, it is increasingly recog nized that many of the proteins involved play an important role in much more common neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), dementia and Parkinson disease (PD) [3,4,5,6,7]
Autophagosomes in particular constitutively form in the distal end of axons and are trans ported retrogradely to the cell soma for degradation [144,145], and any defect disturbing this essential mechanism is likely to result in neuronal pathology. The latter hypothesis is sup ported by the observation that mutations affecting proteins primarily involved in axonal transport cause similar phenotypes as primary autophagy dis orders, probably due to secondary effects on correct autopha gosomal positioning [146,147]. In addition to these basic considerations and in a more clinical context, autophagy has been associated with adultonset neurodegenerative disorders in several ways, nonspecifically through its complex interactions with the potentially toxic protein aggregates implicated in these conditions, and, through primary genetic muta tions directly or indirectly affecting components of the auto phagy machinery: Autophagy plays a role, for example, in the removal of SNCA in PD [149,150], misfolded proteins in ALS [52,151], mutant HTT in Huntington disease (HD) [114,152] and intracellular MAPT/TAU tangles in Alzheimer disease (AD) [153,154], but at the same time these targets of autophagic digestions may impair normal autophagic flux and functioning through their inherent toxicity

Summary

Introduction

Genetic defects affecting cellular pathways with fundamental biological functions are often associated with extensive and not infrequently lethal human multisystem disorders. The latter hypothesis is sup ported by the observation that mutations affecting proteins primarily involved in axonal (including autophagosomal) transport cause similar phenotypes as primary autophagy dis orders, probably due to secondary effects on correct autopha gosomal positioning [146,147] In addition to these basic considerations and in a more clinical context, autophagy has been associated with adultonset neurodegenerative disorders in several ways (for review [148],), nonspecifically through its complex interactions with the potentially toxic protein aggregates implicated in these conditions, and, through primary genetic muta tions directly or indirectly affecting components of the auto phagy machinery (summarized in Table S1): Autophagy plays a role, for example, in the removal of SNCA (synuclein alpha) in PD [149,150], misfolded proteins in ALS [52,151], mutant HTT (huntingtin; mHTT) in Huntington disease (HD) [114,152] and intracellular MAPT/TAU tangles in Alzheimer disease (AD) [153,154], but at the same time these targets of autophagic digestions may impair normal autophagic flux and functioning through their inherent toxicity. Subtle clinical signs or symptoms may be present for years (if not decades) in susceptible patients, indicat ing markers that may allow identification of patients for early treatment [65]

Conclusions and outlook

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