**1. Introduction**

Proteins are linear covalent chains of amino acids. In most proteins, the chain winds in a specific way to adopt a set fold, or "conformation", that is stable and that allows it to function. A number of proteins remain unfolded in their native state and these are referred to as intrinsi‐ cally disordered proteins. These unfolded proteins remain soluble and functional and some exhibit specific ligand binding capability, which can cause them to adopt an induced fold. In contrast to these two functional situations of natively folded and disordered proteins, proteins that are normally folded or disordered can misfold, that is, to fold incorrectly.

Proteins may misfold as a result of enzymatic cleavage, post-translational modification, mutation, overabundance or structural destabilization due to alteration in the tissue environ‐ ment. Accumulation of misfolded proteins can occur more readily when proteostasis mecha‐ nisms that foster correct folding of proteins, such as the chaperone system, and that clear the cell of misfolded proteins, such as the ubiquitin-proteasome system, are compromised [1]. A subset of human proteins appears to have an unusual tendency to misfold and this is recog‐ nized as a central event in a number of human diseases (reviewed by [2]). Improper folding often leads to problems because the misfolded protein cannot perform its normal role (loss of essential function) and because it assembles into oligomeric forms or larger aggregates that are toxic to the cell (gain of harmful function) [3]. The most recognized misfolded conformation is a stacking of β-sheets forming a crossed-β secondary structure that assembles into a linear multimeric fiber called amyloid (reviewed in [2]).

Several neurodegenerative diseases share protein misfolding as an underlying cause [4, 5]. These diseases can be classified based upon the proteins affected [3] while sharing a com‐ mon mechanism of emergence. Protein misfolding in neurodegenerative diseases has been the focus of many reviews; excellent examples are in [5-9]. Therefore, a comprehensive re‐

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view will not be undertaken here. The canonical neurodegenerative diseases are Alzheim‐ er's disease (AD), Parkinson's disease (PD), Huntington's disease, amyotrophic lateral sclerosis and the prion diseases. Although each involves distinct proteins, misfolding has a common role. Huntington's disease is caused by an excessive number of sequential gluta‐ mines near the N terminus of the protein huntingtin. An expansion of the natural glutamine stretch exceeding approximately 33 residues results in Huntington's symptoms and the age of onset of the disease declines with increasing residue number [10-12]. A likely reason for this is the increased propensity for aggregation with increasing polyglutamine length [13]. Amyotrophic lateral sclerosis is a disease associated with the death of the upper and lower motor neurons in the spinal cord, brain stem and motor cortex. The affected neurons accu‐ mulate aggregate protein inclusions that may be causing the cells to die. Mutations in genes encoding superoxide dismutase-1, TAR DNA binding protein 43 and fused in sarcoma/ translation in liposarcoma (FUS/TLS) are implicated in ALS (reviewed in [14]). Prion diseas‐ es display several interesting commonalities with these other neurodegenerative diseases. Prion diseases emerge from misfolded prion protein, which serves as a template for subse‐ quent misfolding of native prion protein with ensuing aggregation and neuron loss. The propagation of pathogenic misfolding from one protein molecule to its healthy neighbours by templating was long considered to be unique to prions; however, recent studies have suggested that molecular templating of misfolded proteins occurs with other neurodegener‐ ative diseases as well. Furthermore, templating is inferred by observation of their spatial spread from select foci in the brain [5, 15, 16]. It is notable that prion diseases, which are in‐ fectious, may occur in animals or humans of all ages, whereas the apparently non-transmis‐ sible protein folding diseases occur mainly with ageing. This implies that a key step in all protein folding disease may be the initial establishment of a misfolded protein in a neuron, whether it is a misfolded protein taken in at any age by infection or misfolding that emerges in a susceptible endogenous protein due to faltering proteostasis with ageing. Therefore, the prevention of misfolding and/or the promotion of disaggregation and refolding of misfold‐ ed proteins *in vivo* appear to be the most direct means of dealing with all these diseases.

In this chapter, the focus is on AD and PD, as these are the two most prevalent neurodege‐ nerative diseases, and the proteins that misfold in these diseases are well studied. AD ac‐ counts for approximately two thirds of all cases of dementia [17]; it leads to cognitive deficits in reasoning, memory, abstraction and motor skills, with eventual death. It is charac‐ terized at the molecular level by extracellular aggregates of a short peptide called amyloid beta (Aβ, and also called beta amyloid), which can form oligomers and larger fibrils with amyloid structure and later emerging intracellular neurofibrillary tangles that are composed of hyperphosphorylated tau protein (reviewed in [18]). In this chapter, Aβ normally refers to Aβ42, which is the 42-residue peptide and also appears to be most toxic form. There is in‐ creasing evidence that the Aβ oligomers have a key and likely causative role in AD. Most compelling are studies showing mutations in the regulatory region or encoded protein se‐ quence in amyloid precursor gene in families predisposed to AD [19-21]. In contrast to AD, PD has been found to involve the misfolding of α–synuclein (αS) into aggregates found in Lewy bodies and Lewy neurites. PD affects the *substantia nigra*, a region of the brain in‐ volved with reward, addiction and movement. Many of the onset symptoms of PD reflect this, and the diagnosis is based on resting tremor, slowness of movement, rigidity and pos‐ tural instability [22]. These two proteins are unrelated in sequence and they have distinct structures in their native form, with Aβ a short mainly unstructured peptide and αS a larger 140-residue protein that is post-translationally modified and that can exist in alternative conformations including a largely α-helical form and a disordered state [23, 24]. In spite of these differences, both proteins misfold and aggregate, and the aggregates of each can be de‐ tected and measured using assays that will be discussed in the section below.

There is growing interest in the development of protein folding modulators that would offer to prevent or alleviate misfolding and to avoid the damage that occurs in neurodegenerative diseases. There has been progress along several avenues, but no magic bullet to date. None‐ theless, there remains substantial untapped diversity among natural products and notably in marine resources. With a focus on Aβ and αS, which are implicated in AD and PD, respectively, this chapter will examine natural agents that may prevent or ameliorate protein misfolding diseases, with particular attention to the potential of marine resources for possible discovery and development.
