Table 1.

MtDNA methylation investigations in neurodegenerative diseases.

Experimental model	Method of measurement	mtDNA region investigated	Observation	References
Brain and spinal cord motor neurons of mice, and post-mortem human cortex of 12 ALS patients	Immunohistochemistry	Global 5-mC levels	Increased DNMT activity and 5-mC levels in motor neurons.	(22)
Spinal cord and skeletal muscle of ALS mice and non transgenic (non-tg) mice	Pyrosequencing	D-loop and 16S rRNA	Higher methylation levels of 16S rRNA gene in spinal cord and skeletal muscle of mice with G37R and G93A SOD1 mutations, and lower methylation in SOD1 wild-type mice respect to non-tg mice. Decreased D-loop methylation in spinal cord of mice with G93A SOD1 mutation respect to non-tg mice.	(24)
Superior and middle temporal gyrus (SMTG) and cerebellum (CER) of 7 late-onset AD patients and 5 control subjects	Immunohistochemistry	Global 5-hmC levels	A trend toward a significant increase in SMTG mtDNA of AD patients compared to control subjects.	(60)
Entorhinal cortex of 8 AD-related pathology patients and 8 control subjects, cerebral cortex of AD mouse model, and substantia nigra of 10 PD patients and 10 control subjects	Pyrosequencing	Methylation and hydroxymethylation levels of D-loop region, MT-ND1, and MT-ND6 genes	Increased D-loop methylation levels in AD related pathology patients respect to control subjects. Dynamic pattern of D-loop methylation in mice along with Alzheimer disease pathology progression. Decreased D-loop methylation found in PD patients respect to control subjects. MT-ND1 less methylated in AD-related patients than in control samples.	(61)
Peripheral blood of 133 late-onset AD patients and 130 matched controls	Methylation sensitive-high resolution melting	D-loop region	Significant reduction of D-loop methylation in AD patients.	(62)
Peripheral blood of 114 individuals, including 54 ALS patients, 28 presymptomatic carriers, and 32 noncarrier family members	Methylation sensitive-high resolution melting	D-loop region	SOD1 mutation carriers showed a significant decrease in D-loop methylation levels. Inverse correlation between D-loop methylation levels and mtDNA copy number.	(37)