**1. Introduction**

Oxidative damage can come from harmful environments such as chemical agents and ionizing radiation, but the major oxidative damage is also caused by internally sourced reactive oxygen species (ROS) generated from the natural metabolic processes in living cells. As the brain has a relatively higher oxygen demand and lower levels of antioxidants than other organs, ROS generates mainly DNA damage in the brain [1]. Numerous studies show that the accumulation of neuronal DNA damage contributes to the progress of aging [2]. DNA bases frequently undergo lesions through modification by alkylation, oxidation, and deamination [3]. To protect against these destructive adducts, cells have developed an antioxidant defense system to be expressed by enzymes involved in base excision repair (BER). The imbalance between clearance and generation of ROS plays a critical role in disease pathogenesis. Except for healthy aging, insufficient DNA repair has been tightly associated with neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic

lateral sclerosis (ALS) [4–9]. The elevated DNA strand breaks and the decreased DNA double-strand breaks (DSBs) repair proteins have been described in AD brains.

Additionally, the increase in β-amyloid (Aβ) and neurofibrillary tangles (NFTs) is closely linked to decreased oxidative damage—an early event in AD that decreases with disease progression [10]. What is more, the lesions to mitochondrial, a major source of ROS, have been reported in the PD cases, and mitochondrial dysfunctions have been associated with the disease pathophysiology. Historically, the first investigation involving mitochondria in PD relates to the observation that the presence of an impairment of complex I in the different forms of PD and Parkinsonism [11]. Dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and PD have been aggregated conceptually as Lewy body disease (LBD) [12].

Striatal dopaminergic dysfunction probably is involved in both AD and LBD, while degeneration of nigrostriatal dopaminergic neurons is the classic pathology of PD; striatal dopaminergic dysfunction may also promote the motor manifestations of AD. The striatum consists of several subregions—caudate and putamen. The caudate nucleus is essential in many behaviors, including procedural learning and working memory; the dorsal posterior putamen receives its primary input from the motor and sensorimotor cortices and regulates the motor circuits [13–15]. Dopamine generates hydroxyl radical (•OH) through Fenton reactions in the presence of iron, which is believed to be responsible for the oxidative damage to lipids, proteins, and DNA in living cells and dopaminergic neurons [16]. Besides, as a chelator, dopamine can form different complexes with Fe(II) and Fe(III), decreasing catalytic productions of ROS [17]. Dopamine compartmentalization has been described by the vesicular monoamine transporter 2 (VMAT2)—correlates with dopaminergic neurons' vulnerability in Parkinsonism neurodegeneration [18]. There are close interactions among oxidative damage and dopamine concentration, and the antioxidant role of VMAT2 should be given more attention. Oxidative stress induced by genetics has been linked to the Y-chromosome gene products that modulate dopamine biosynthesis and motor function [19]. Further, DNA damage is associated with acceleration of the rate of aging, causing a variety of early symptoms such as gray hair, kidney disease, cataracts, osteoporosis, and neuronal atrophy [20]—factors which determine the health or disease people's life span and age at the onset of diseases.

Therefore, it is clear that there is an appreciable need for a better understanding of the correlations between oxidative damage and neurodegenerations. In this chapter, the striatal DNA damage was first focused, and its brain region concentrations in neurodegenerative diseases will be discussed with parallel changes of dopamine levels and VMAT2 densities. Moreover, original data on the association among striatal DNA damages, sex, life span, and the age of onset of diseases in neurodegenerative patients will be presented.
