Neurodegenerative diseases – Understanding their molecular bases and progress in the development of potential treatments

doi:10.1016/j.ccr.2014.03.026

Coordination Chemistry Reviews

Volume 284, 1 February 2015, Pages 298-312

https://doi.org/10.1016/j.ccr.2014.03.026 Get rights and content

Highlights

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Parkinson's, Alzheimer's or prion diseases have at least three common denominators.
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First, progressive loss of neuron function, that leads to cognitive decline.
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Second, the molecular basis of the disease, which involves metalloprotein misfolding and aggregation (amyloid beta, alpha synuclein, prion protein), metal ion (Cu²⁺, Zn²⁺, Fe³⁺) imbalance that results in oxidative stress.
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Third, currently, the lack of a therapeutic able to reverse or at least stop the progression of symptoms.
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In this work, all these problems are collectively discussed..

Abstract

Neurodegenerative diseases such as Parkinson's, Alzheimer's, and prion diseases have at least three common denominators: (i) progressive loss of neuron function, which leads to cognitive decline; (ii) the molecular basis of the disease, which involves metalloprotein misfolding and aggregation (amyloid beta, alpha synuclein, and prion protein), or metal ion (Cu²⁺, Zn²⁺, and Fe³⁺) imbalances that result in oxidative stress; and (iii) the current lack of a therapy to reverse or stop the progression of symptoms. These problems are discussed collectively in the present review. First, the molecular bases of these three diseases are explained in brief, with a special focus on the role of coordination chemistry in each case. Next, several commercial drugs that can be used to treat the symptoms are presented, i.e., those that do not aim to achieve metal ion homeostasis, which may be less well known in the bioinorganic community; and those that aim to achieve metal ion chelation, including the molecular scaffolds of those currently in clinical trials and the most promising targets that are still being studied in vitro. Another very important issue summarized in this review encompasses the strategies that have been developed to overcome the blood–brain barrier (BBB) and deliver drugs inside the brain. The BBB is a major obstacle in the development of drugs for treating central nervous system diseases. The BBB includes anatomical, physicochemical, and biochemical mechanisms that control the exchange of molecules between the blood and brain, thereby making the BBB virtually impermeable to drugs that might be used to treat neurodegenerative diseases. The non-optimistic nature of this review has a dual role. First, we present a true picture of the progress in the development of potential therapeutics. Second, we aim to encourage further targeted research in this area.

Graphical abstract

Introduction

According to the World Health Organization, the three main causes of death in developed countries are cardiovascular disease, cancer, and neurodegenerative diseases. Bioinorganic chemistry has an important role in the latter two illnesses, where it facilitates the design and improved understanding of the principles of metal-based drugs (e.g., the well-known cisplatin, which is an anticancer drug) and metal chelators (in neurodegenerative diseases). In this review, we focus on the roles of metal ions in neurodegeneration by summarizing the molecular basis of the disease, the impact of metal ions during pathogenesis, the commercially available (non-metal-related) drugs, potential metal chelation treatments, and the main obstacle to their application: the blood–brain barrier (BBB).

The role of metal ions in neurodegenerative diseases is a rapidly expanding subfield of bioinorganic chemistry. Recently, several comprehensive reviews have been published on the roles of metal ions in Parkinson's, Alzheimer's, and prion diseases [1], [2], [3], as well as metal ion chelators that might be used as potential therapeutics [4], [5].

The first sections of this review explain the molecular basis of the three diseases. Each of these sections begins with a short, descriptive outline of the disorder, which briefly summarizes the symptoms and the social scale of the problem. Next, the molecular bases of the diseases are clarified, where we describe the proteins involved in neurodegeneration and their complex relationships with metal ions. The coordination sites are highlighted and the possible metal ions involved are explained in detail. The later sections focus on possible treatment strategies by summarizing the traditional, non-metal-related drugs that are available in clinics and discussing the recent progress made in the design of possible therapeutics based on metal ion chelators. Special attention is given to the results of the clinical trials of two Prana Biotechnology products (clioquinol and PBT2) and to the possible modifications that can be made to functionalize metal-chelating molecules with additional therapeutic moieties, or with groups that may make them more permeable through the BBB. This major obstacle, the BBB, is indeed the biggest problem that needs to be overcome to facilitate the design of drugs to combat neurodegeneration. We focus on this issue in Section 6. This review provides a comprehensive summary of all of these areas in one study. In particular, the sections that describe the commercially available drugs and the problems of overcoming BBB may be fairly novel and they provide a useful synopsis of this area for coordination chemists.

Section snippets

Pathology of alpha-synuclein in Parkinson's disease

Parkinson's disease (idiopathic, essential, or primary) is named after the British physician James Parkinson, who described the “shaking palsy” in 1817, although the disease itself has probably existed for many centuries because similar symptoms are described in texts related to Chinese medical practice that date from several centuries BC. In industrialized countries, the current prevalence of Parkinson's disease (PD) is ca 1% in people aged >60 years [6]. The prevalence rises sharply with age

Amyloid beta in Alzheimer's disease

Alzheimer's disease (AD), the most common form of neurodegenerative disease, was first described by the German psychiatrist Alois Alzheimer in 1906 [39]. AD is usually diagnosed in people in their late sixties, although the rare form of early-onset AD can occur much earlier. AD is currently the sixth most common cause of death in the USA. Worldwide, the statistical prevalence of AD is difficult to estimate precisely, but >26 million is a reasonable estimate and this is expected to triple by

Misfolded prion proteins

Prion diseases are fatal neurodegenerative disorders that are characterized by progressive brain degeneration, which is caused by a protein infectious agent that induces protein conformational changes [62]. They are the most rare of the neurodegenerative diseases and they affect only one person per million [63]. Human prion diseases include Creutzfeldt-Jakob (CJD), Gerstmann-Sträussler-Scheinker, fatal familial insomnia, and kuru diseases [64], [65]. The most common animal version of the

Recommended traditional therapies

To provide a comprehensive overview of these diseases, it is necessary to understand the current state of knowledge at the molecular level, the impact of metal ion binding on the pathogenesis of the diseases, and details of clinical trials and future potential therapies, while it is also important to know how these disorders are currently treated in the clinic. The next three sections (one for each disease) review the recommended traditional therapies. The next section discusses the biggest

Blood–brain barrier: the major obstacle

In recent decades, significant progress has been made in understanding the molecular basis of neurodegeneration, particularly the target proteins and the metals that should be chelated. However, the BBB remains the biggest obstacle to exploiting this knowledge and developing drugs to treat diseases of the CNS.

The BBB includes anatomical, physicochemical, and biochemical mechanisms that control the exchange of molecules between the blood and brain [118]. These mechanisms make the BBB virtually

Possible metal-related therapeutics

The underlying concept of using metal chelators as therapeutics for neurodegenerative diseases is quite simple, because it assumes that metal ions are the main causes of pathogenic protein deposits and abnormal oxidative stress. Therefore, if metal homeostasis is preserved, or if there is not an excess of metal ions in the brain, the pathogenic protein forms would not be present. Moreover, small and lipophilic metal-chelating molecules can be designed, which have an increased likelihood of

Concluding remarks

At present, it is well known that neurodegenerarative diseases are major medical and social problems and predictions of their future frequency are not optimistic. In this review, we provided basic information about three neurodegenerative disorders: Parkinson's, Alzheimer's, and prion diseases. We focused on the molecular basics and the involvement of metal ions in each disease, with particular considerations of the common drugs that are currently prescribed in clinics and potential metal

Acknowledgments

M. Rowinska-Zyrek was supported by a scholarship from the Foundation For Polish Science.

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder preceded by Alzheimer’s disease. Parkinson’s disease is characterized by the progressive loss of neurons in the substantia nigra, and the formation of Lewy bodies, which its main component is the protein α-synuclein [2,3]. This protein is 140-amino acid long and is encoded by the SNCA gene.
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ReviewNeurodegenerative diseases – Understanding their molecular bases and progress in the development of potential treatments

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Pathology of alpha-synuclein in Parkinson's disease

Amyloid beta in Alzheimer's disease

Misfolded prion proteins

Recommended traditional therapies

Blood–brain barrier: the major obstacle

Possible metal-related therapeutics

Concluding remarks

Acknowledgments

Coord. Chem. Rev.

Coord. Chem. Rev.

Coord. Chem. Rev.

Lancet Neurol.

J. Biol. Chem.

Coord. Chem. Rev.

Biochem. Biophys. Res. Commun.

Coord. Chem. Rev.

Coord. Chem. Rev.

Neuron

J. Biol. Chem.

Neurosci. Lett.

Coord. Chem. Rev.

Neurobiol. Aging

Alzheimer's Dement.

Neuron

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Inorg. Chem.

Clin. Infect. Dis.

Science

Biochim. Biophys. Acta

J. Mol. Med.

Chem. Rev.

J. Neurochem.

Biochem. J.

Dalton Trans.

Br. J Pharmacol.

Coord. Chem. Rev.

Neurology

J. Neurol. Neurosurg. Psychiatr.

Br. Med. Bull.

J. Neurochem.

Proc. Natl. Acad. Sci. U.S.A.

Proc. Natl. Acad. Sci. U.S.A.

Science

Biochemistry

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Biochemistry

Inorg. Chem.

Metallomics

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Biochemistry

Dalton Trans.

Chem. Soc. Rev.

Dalton Trans.

FASEB J.

Review
Neurodegenerative diseases – Understanding their molecular bases and progress in the development of potential treatments