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

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.

Keywords: autophagy; cellular trafficking; neurodegenerative disorders; congenital disorders of autophagy; neurodevelopmental disorders.

Figure 1.

The autophagy pathway and its relation to other intracellular regulatory and trafficking pathways. (A) Schematic representation of the autophagy pathway and the key steps involved, ranging from phagophore formation utilizing lipid membranes from various donor compartments (such as ER, Golgi and mitochondria), autophagosome formation, autolysosomal fusion and cargo degradation, and, finally, autophagic lysosomal reformation (ALR). Gene mutations can disturb any (and often multiple) part(s) of the complex autophagic machinery; the proteins most commonly implicated in the congenital disorders of autophagy are indicated in red, in relation to the part of the autophagy pathway affected. Close relations to the MTOR pathway (B), the endo-lysosomal pathway (C) and (neuronal) axonal transport (D) emphasize that any genetic defect primarily affecting these intricately linked cellular processes may cause clinical presentations very similar to those concerning the primary autophagy machinery. Along similar lines, primary disturbances of other cellular processes and structures essential for the normal functioning of autophagy (for example, disturbances of lipid metabolism affecting the membrane sources required for phagophore formation, or of the glycosylation of autophagy proteins) may have similar biological and clinical consequences. Figure created with BioRender.com.

Figure 2.

Key clinical and pathological features of EPG5-related Vici syndrome, the paradigmatic congenital disorder of autophagy. Patients of Turkish (A) and Indian (E) descent with hypopigmentation relative to ethnic background. Although neurological findings may be subtle at an early age (A), more severely affected patients may show coarse facial features suggestive of a storage disorder (E) and neurological deterioration from early infancy. Cataracts are common. Thalamic changes characterized by low signal on T2- (B) (asterisks) and high signal on T1-weighted brain images (F) (asterisks) may be observed in a proportion of patients and have also been reported in some lysosomal storage disorders. On light microscopy, (C) muscle biopsy findings are characterized by increased variability in fiber size and the presence of numerous internalized and central nuclei (arrows), resembling centronuclear myopathy and X-linked myotubular myopathy (scale bar: 50 μm). On the ultrastructural level (D), in skeletal muscle there are numerous vacuoles and evidence of ongoing exocytosis (arrow) (scale bar: 500 nm). A peripheral neuropathy characterized by marked reduction of myelinated fibers (arrows) on sural nerve biopsy stained with Toluidine Blue (G) has been reported in few patients (scale bar: 50 μm). On confocal immunohistochemistry of EPG5-mutated fibroblasts treated with bafilomycin A₁ (H), compared to normal fibroblasts where numerous LC3-positive autophagosomes are found engulfed by the LAMP1-positive vesicular structures (data not shown), relatively small LC3-positive puncta (in red) only sporadically colocalize with LAMP1 (in green, arrowhead shows colocalization), with many isolated LC3-positive puncta (arrows). In addition, in EPG5-mutated fibroblasts the LC3 signal is seen mainly at the rim of LAMP1-positive structures rather than centrally. These findings are indicative of an autophagosome-lysosome fusion defect (scale bar: 5 μm).

Figure 3.

Neurodevelopmental and neurodegenerative disorders with defects in intracellular trafficking and autophagy. The accumulation of abnormal protein aggregates and defective organelles (in particular mitochondria) with age is counterbalanced by intracellular quality control mechanisms including mitophagy and aggregate removal through autophagy and/or the ubiquitin-proteasome (UPS) system. In genetic conditions impairing the effective actions of these intracellular pathways, the balance is shifted, resulting in neurodegenerative changes usually occurring later in life. Early-onset neurodevelopmental and adult-onset neurodegenerative disorders with defects in autophagy thus represent a highly interconnected spectrum of disorders associated with premature neuronal aging presenting throughout life.