Table 2.

Examples of autophagy alteration in degenerating neurites in different neurodegenerative disorders.

Disease (Organism/animal or cell model)	Tissues/cells	Effects	Phenotype	Refs
AD
Human patients	Neocortex	Undermined.	Autophagosomes and other prelysosomal autophagic vacuoles accumulate in degenerating neurites.	[14]
	Hippocampus and inferior temporal cortex	Undermined.	Enhanced immunoreactivity of Atg12 in tau-immunopositive dystrophic neurites and some neurofibrillary tangles.	[15]
	Hippocampus	Undermined.	APP accumulates in the lysosomal system of the degenerating neurites present in senile plaques.	[16]
	Biopsied brain material	Undermined.	PS1 immunoreactivity is identified in autophagic vacuoles in degenerating neurites.	[17]
APP, PS/APP transgenetic mice	Cerebral cortex, hippocampus	Beneficial.	Autophagosomes and autolysosomes accumulate in degenerating neurites. Recovery of lysosomal proteolysis reverses axonal dystrophy and enhances maturation of accumulated autophagosomes.	[17, 31, 40, 72]
Lysosomal proteolysis inhibition	Mouse cortical neurons	Beneficial.	Lysosomal dysfunction disrupts axonal transport of degradative organelles and causes Alzheimer-like neurite dystrophy.	[31]
ALS
SOD1 mutant mice	Spinal cord motor neurons	Harmful.	Autophagic vacuoles accumulated in degenerating axons. Autophagy stimulation accelerates the motor neuron degeneration.	[11]
Human patients	Motor neurons	Undermined.	The autophagy features were also found in close association with the characteristic inclusions of ALS.	[95]
Epilepsy
Atg7 conditional knockout mice	Forebrain neurons	Beneficial.	Atg7-deficiency promotes the development of spontaneous seizures.	[81]
Human TSC patients	Brain tissues	Undermined.	Autophagy is suppressed in brains.	[81]
HD
Human patients	Striatum	Beneficial.	Beclin1-positive inclusion-like deposits accumulate in axon or neuropil of HD samples. However, striatal neurons in normal control brains show diffuse immunoreactivity for Beclin1.	[20]
Hdh140Q/ΔQ mice	Striatum	Beneficial.	LC3 colocalizes with neuropil htt aggregates in the Hdh140Q/ΔQ striatum at 1 and 2 years of age, and such phenomenon is absent in the Hdh140Q/+ striatum.	[78]
Inherited ataxias
Human patients	Cerebral and brainstem	Undermined.	Widespread axonal aggregates, immunopositive for autophagy associated shuttle protein p62, appear in fiber tracts known to undergo neurodegeneration in SCA3 brains.	[96]
Lurcher mice, atg5 and atg7 conditional knockout mice	DCN	Tentatively Beneficial.	Autophagy serves as an early stress response in axonal dystrophy. Atg7 and Atg5 are both required for the maintenance of axonal homeostasis and the prevention of axonal degeneration.	[8, 25, 97]
pcd mutant mice	DCN	Harmful.	Autophagosomes accumulate in Purkinje cell axons. Increased or aberrant mitophagy may contribute to the Purkinje cell degeneration in pcd mice.	[9]
PD
Human patients	SNpc	Beneficial.	LC3 immunoreactivity is detected in a-synuclein-positive Lewy neurites, a neuropathological feature of PD indicative of axonal pathology.	[18, 19]
G2019S LRRK2 mutant mice	Cerebral cortex, striatum	Undermined.	Early and late autophagosomes accumulate in axons and synapses in animals with advanced age.	[57]
Atg7 conditional knockout mice	Midbrain DA neurons	Beneficial.	Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of a-synuclein and LRRK2 in the brain.	[79, 80]
G2019S LRRK2 overexpression	Mouse cortical neurons	Harmful.	LRRK2 mutants selectively cause dendrite retraction due to calcium dysregulation and induction of dendritic mitophagy.	[54,55]
G2019S LRRK2 overexpression	SH-SY5Y cells	Harmful.	Autophagosomes accumulate in neurites. Autophagy inhibition prevents neuritic retraction, whereas autophagy stimulation potentiates LRRK2-induced neuritic shortening.	[56]
MPP+ intoxication	Mouse DA neurons	Undermined.	Neuritic degeneration and autophagy occurs before cell body loss.	[98]
Prion disease
Human patients	Brain tissues obtained from CJD patients	Undermined.	Autophagosomes appear in the affected synapses.	[27]
CJD-infected hamsters or GSS- infected mice	Parietal cortex, corpus callosum, hippocampus, thalamus, cerebellum, brainstem	Undermined.	The major target of autophagy is dystrophic neurites, mostly dendrites but also axonal terminals and preterminals.	[59]
Scrapie prion strain infection	Mouse brain aggregate	Beneficial.	The LC3-II immunoreactivity is seen as deposits scattered throughout the neuropil.	[99]

AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; CJD, Creutzfeldt-Jakob disease; DA, dopamine; DCN, deep cerebellar nuclei; GSS, Gerstmann-Sträussler-Scheinker; HD, Huntington’s disease; Hdh^140Q/ΔQ, full-length htt lacking its polyglutamine stretch in a knockin mouse model for HD; htt, huntingtin; LRRK2, leucine rich repeat kinase 2; MPP⁺, 1-methyl-4-phenylpyridinium ion; pcd, Purkinje cell degeneration; PD, Parkinson’s disease; PS1, presenilin 1; PS/APP, presenilin/amyloid precursor protein; SCA3, spinocerebellar ataxia type 3; SNpc, substantia nigra pars compacta; TSC, tuberous sclerosis complex.